Disease Information

General Information of the Disease (ID: DIS00052)
Name
Acute myeloid leukemia
ICD
ICD-11: 2A60
Resistance Map
Type(s) of Resistant Mechanism of This Disease
  ADTT: Aberration of the Drug's Therapeutic Target
  DISM: Drug Inactivation by Structure Modification
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  IDUE: Irregularity in Drug Uptake and Drug Efflux
  MRAP: Metabolic Reprogramming via Altered Pathways
  RTDM: Regulation by the Disease Microenvironment
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Investigative Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
Anthracyclines
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Transforming growth factor beta 1 (TGFB1) [1]
Metabolic Type Lipid metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Anthracyclines
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myeloid leukemia
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.40E-07
Fold-change: 6.20E-01
Z-score: 6.08E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation TGF-beta signaling pathway Activation hsa04350
In Vitro Model K562/ADR cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX8 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1) [1]
Metabolic Type Lipid metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Anthracyclines
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myeloid leukemia
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.40E-07
Fold-change: 6.20E-01
Z-score: 6.08E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation TGF-beta signaling pathway Activation hsa04350
In Vitro Model HL60/ADR cells Blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX7 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1) [1]
Metabolic Type Lipid metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Anthracyclines
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myeloid leukemia
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.40E-07
Fold-change: 6.20E-01
Z-score: 6.08E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation TGF-beta signaling pathway Activation hsa04350
In Vitro Model K562 cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX6 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1) [1]
Metabolic Type Lipid metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Anthracyclines
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myeloid leukemia
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.40E-07
Fold-change: 6.20E-01
Z-score: 6.08E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation TGF-beta signaling pathway Activation hsa04350
In Vitro Model HL-60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX5 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1) [1]
Metabolic Type Lipid metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Anthracyclines
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myeloid leukemia
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.40E-07
Fold-change: 6.20E-01
Z-score: 6.08E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation TGF-beta signaling pathway Activation hsa04350
In Vitro Model KG-1 A cells Blood Homo sapiens (Human) CVCL_0374
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX4 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1) [1]
Metabolic Type Lipid metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Anthracyclines
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myeloid leukemia
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.40E-07
Fold-change: 6.20E-01
Z-score: 6.08E+00
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation TGF-beta signaling pathway Activation hsa04350
In Vivo Model HCC patients Homo Sapiens
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Approved Drug(s)
31 drug(s) in total
Click to Show/Hide the Full List of Drugs
Cytarabine
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Transforming growth factor beta 1 (TGFB1) [1]
Metabolic Type Lipid metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myeloid leukemia
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.40E-07
Fold-change: 6.20E-01
Z-score: 6.08E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation TGF-beta signaling pathway Activation hsa04350
In Vitro Model KG-1 A cells Blood Homo sapiens (Human) CVCL_0374
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX9 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1) [1]
Metabolic Type Lipid metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myeloid leukemia
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.40E-07
Fold-change: 6.20E-01
Z-score: 6.08E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation TGF-beta signaling pathway Activation hsa04350
In Vitro Model K562/ADR cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX13 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1) [1]
Metabolic Type Lipid metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myeloid leukemia
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.40E-07
Fold-change: 6.20E-01
Z-score: 6.08E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation TGF-beta signaling pathway Activation hsa04350
In Vitro Model HL60/ADR cells Blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX12 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1) [1]
Metabolic Type Lipid metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myeloid leukemia
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.40E-07
Fold-change: 6.20E-01
Z-score: 6.08E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation TGF-beta signaling pathway Activation hsa04350
In Vitro Model K562 cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX11 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1) [1]
Metabolic Type Lipid metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myeloid leukemia
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.40E-07
Fold-change: 6.20E-01
Z-score: 6.08E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation TGF-beta signaling pathway Activation hsa04350
In Vitro Model HL-60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX10 expression.
Key Molecule: Transforming growth factor beta 1 (TGFB1) [1]
Metabolic Type Lipid metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myeloid leukemia
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.40E-07
Fold-change: 6.20E-01
Z-score: 6.08E+00
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation TGF-beta signaling pathway Activation hsa04350
In Vivo Model HCC patients Homo Sapiens
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Key Molecule: Cytochrome P450 family 1 subfamily A member 1 (CYP1A1) [16]
Metabolic Type Mitochondrial metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cushing syndrome Activation hsa04934
In Vitro Model SHI-1 cells Bone marrow Homo sapiens (Human) CVCL_2191
Skm1 cells Blood Homo sapiens (Human) CVCL_0098
U937 cells Blood Homo sapiens (Human) CVCL_0007
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description The data analysis reveals that the AHR signaling pathway is activated in AML patients. Furthermore, there is a correlation between the expressions of AHR and mitochondrial oxidative phosphorylation genes.In vitroexperiments show that enhancing AHR expression in AML cells increases mitochondrial oxidative phosphorylation and induces resistance to cytarabine. Conversely, reducing AHR expression in AML cells decreases cytarabine resistance.
Key Molecule: Cytochrome P450 family 1 subfamily B member 1 (CYP1B1) [16]
Metabolic Type Mitochondrial metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cushing syndrome Activation hsa04934
In Vitro Model SHI-1 cells Bone marrow Homo sapiens (Human) CVCL_2191
Skm1 cells Blood Homo sapiens (Human) CVCL_0098
U937 cells Blood Homo sapiens (Human) CVCL_0007
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description The data analysis reveals that the AHR signaling pathway is activated in AML patients. Furthermore, there is a correlation between the expressions of AHR and mitochondrial oxidative phosphorylation genes.In vitroexperiments show that enhancing AHR expression in AML cells increases mitochondrial oxidative phosphorylation and induces resistance to cytarabine. Conversely, reducing AHR expression in AML cells decreases cytarabine resistance.
Key Molecule: Isocitrate dehydrogenase [NADP] mitochondrial (IDH2) [17]
Metabolic Type Glucose metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Longevity regulating pathway - multiple species Activation hsa04213
In Vitro Model AML cells N.A. Homo sapiens (Human) N.A.
HL-60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
IDH2 mutant AML cells Blood Homo sapiens (Human) CVCL_S481
KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
Experiment for
Drug Resistance		 IC50 assay
Mechanism Description The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells.
Key Molecule: Isocitrate dehydrogenase [NADP] mitochondrial (IDH2) [17]
Metabolic Type Glucose metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Longevity regulating pathway - multiple species Activation hsa04213
In Vivo Model AML cell-transplanted tumor nude mice with IDH2 mutations Mice
Experiment for
Drug Resistance		 Tumor volume assay
Mechanism Description The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-335 [15]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
Nodal/TFG-alpha signaling pathway Regulation N.A.
Wnt/alpha -catenin signaling pathway Regulation N.A.
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 Relapse-free survival and overall survival assay
Mechanism Description The expression levels of miR-335 in bone marrow and serum samples from adult patients with AML (except M3) were significantly associated with the Ara-C-based chemotherapy response and clinical outcome after treatment.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [18]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K/Akt/mTOR signaling pathway Regulation N.A.
In Vitro Model HL-60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
In Vivo Model SPF-grade (BALB/C) nude mice model Mus musculus
Experiment for
Molecule Alteration		 RT-qPCR; Glycolysis metabolic enzyme assay; Flow cytometry; Western blot assay; Transcriptome sequencingc assay
Experiment for
Drug Resistance		 Cell proliferation assay; Drug sensitivity testing
Mechanism Description OE-IDH2 in AML cells, enhances resistance to the Ara-C, promotes cell proliferation and glycolysis, and inhibits apoptosis. KD-IDH2 exhibits opposite effects. Both IDH2 mutations and OE-IDH2 produce similar effects on these cellular processes. The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells. Transcriptome sequencing results indicate an enrichment of the PI3K/Akt signaling pathway in IDH2-mutant AML cells. BEZ235 significantly inhibits the expression of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), mTOR, glycolytic metabolism, and Ara-C resistance both in vitro and in vivo. Overexpression and mutation of IDH2 coordinate with the Warburg effect through the PI3K/Akt/mTOR pathway to promote Ara-C resistance in AML.
Key Molecule: Isocitrate dehydrogenase [NADP] mitochondrial (IDH2) [18]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K-Akt signaling pathway Activation hsa04151
In Vitro Model HL-60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The IDH2 mutations are involved in Ara-C resistance by affecting the process of glycolysis in AML, and the PI3K-Akt signaling pathway plays an important role in this process. These pathways are expected to be important targets for targeted therapeutic intervention in the AML setting.
Key Molecule: Acetyl-CoA acetyltransferase 2 (ACAT2) [19]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation DNA Damage Response Mechanism Regulation N.A.
In Vitro Model MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM-13 cells Peripheral blood Homo sapiens (Human) CVCL_2119
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
TF-1 cells Blood Homo sapiens (Human) CVCL_0559
Experiment for
Molecule Alteration		 RT-qPCR; Western blot assay
Experiment for
Drug Resistance		 MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
Mechanism Description DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress. Especially, PPP1R15A is mainly involved in the recovery of the cells from stress and it was the only DDR gene upregulated in AML patients.
Key Molecule: Acetyl-CoA acetyltransferase 2 (ACAT2) [19]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation DNA Damage Response Mechanism Regulation N.A.
In Vitro Model MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM-13 cells Peripheral blood Homo sapiens (Human) CVCL_2119
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
TF-1 cells Blood Homo sapiens (Human) CVCL_0559
Experiment for
Molecule Alteration		 RT-qPCR; Western blot assay
Experiment for
Drug Resistance		 MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
Mechanism Description DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress.Using PCR arrays we observed an upregulation of of several DDR genes (CDKN1A, GADD45A, GADD45G, EXO1, and PPP1R15A) in KASUMI-1 and MV4-11 cell lines that survived following treatment with Idarubicin and Cytarabine.
Key Molecule: Growth arrest and DNA damage-inducible protein GADD45 gamma (GADD45G) [19]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation DNA Damage Response Mechanism Regulation N.A.
In Vitro Model MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM-13 cells Peripheral blood Homo sapiens (Human) CVCL_2119
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
TF-1 cells Blood Homo sapiens (Human) CVCL_0559
Experiment for
Molecule Alteration		 RT-qPCR; Western blot assay
Experiment for
Drug Resistance		 MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
Mechanism Description DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress.Using PCR arrays we observed an upregulation of of several DDR genes (CDKN1A, GADD45A, GADD45G, EXO1, and PPP1R15A) in KASUMI-1 and MV4-11 cell lines that survived following treatment with Idarubicin and Cytarabine.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Programmed cell death protein 4 (PDCD4) [3]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myelocytic leukemia
The Studied Tissue Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 4.63E-03
Fold-change: 7.01E-02
Z-score: 2.85E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description AMO-miR-21 significantly sensitizes HL60 cells to Ara-C byinducing apoptosis and these effects of AMO-miR-21 may be partially due to its up-regulation ofPDCD4.
Key Molecule: High mobility group protein B1 (HMGB1) [7]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myelocytic leukemia
The Studied Tissue Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 3.67E-02
Fold-change: -9.69E-03
Z-score: -2.10E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell migration Inhibition hsa04670
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.
Key Molecule: Klotho (KL) [20]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKTsignaling pathway Inhibition hsa04151
Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
In Vitro Model KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
K562 cells Blood Homo sapiens (Human) CVCL_0004
HK-2 cells Kidney Homo sapiens (Human) CVCL_0302
Experiment for
Molecule Alteration		 RT-PCR; Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Transfection of the mimic miR-126-5p into the AML cell line, kG-1, resulted in a decrease in the sensitivity to cytarabin and the expression level of klotho mRNA as well as the elevation in the phosphorylation of Akt. The results of the present study demonstrated that higher expression levels of miR-126-5p/3p in patients with AML resulted in a poorer prognosis. Furthermore, miR-126-5p elevated the phosphorylation of Akt.
Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [7]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell migration Inhibition hsa04670
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-126-5p [20]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKTsignaling pathway Inhibition hsa04151
Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
In Vitro Model KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
K562 cells Blood Homo sapiens (Human) CVCL_0004
HK-2 cells Kidney Homo sapiens (Human) CVCL_0302
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Transfection of the mimic miR-126-5p into the AML cell line, kG-1, resulted in a decrease in the sensitivity to cytarabin and the expression level of klotho mRNA as well as the elevation in the phosphorylation of Akt. The results of the present study demonstrated that higher expression levels of miR-126-5p/3p in patients with AML resulted in a poorer prognosis. Furthermore, miR-126-5p elevated the phosphorylation of Akt.
Key Molecule: hsa-mir-181 [7]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell migration Inhibition hsa04670
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.
Key Molecule: hsa-let-7a [21]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell growth Activation hsa05200
Cell invasion Activation hsa05200
Epithelial mesenchymal transition signaling pathway Activation hsa01521
In Vitro Model Molm13 cells Blood Homo sapiens (Human) CVCL_2119
OCI-AML3 cells Blood Homo sapiens (Human) CVCL_1844
In Vivo Model AML nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Xenografts of primary human AML cells engineered to overexpress let-7a exhibited enhanced sensitivity to cytarabine.
Key Molecule: Bcl-2-like protein 11 (BCL2L11) [22]
Sensitive Disease Myeloid leukemia [ICD-11: 2A60.4]
Sensitive Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
U937 cells Blood Homo sapiens (Human) CVCL_0007
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description One of the predicted targets of miR-32 lies in the 3' untranslated region (UTR) of BCL2L11 gene, which encodes the pro-apoptotic protein Bim, miR-32 blockade is sufficient to elevate Bim expression and sensitize AML cells to chemotherapy-induced apoptosis.
Key Molecule: hsa-mir-32 [22]
Sensitive Disease Myeloid leukemia [ICD-11: 2A60.4]
Sensitive Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
U937 cells Blood Homo sapiens (Human) CVCL_0007
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description One of the predicted targets of miR-32 lies in the 3' untranslated region (UTR) of BCL2L11 gene, which encodes the pro-apoptotic protein Bim, miR-32 blockade is sufficient to elevate Bim expression and sensitize AML cells to chemotherapy-induced apoptosis.
Key Molecule: hsa-mir-21 [3]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Cytarabine
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description AMO-miR-21 significantly sensitizes HL60 cells to Ara-C byinducing apoptosis and these effects of AMO-miR-21 may be partially due to its up-regulation ofPDCD4.
Ketorolac
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [2]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Ketorolac
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myelocytic leukemia
The Studied Tissue Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 4.70E-06
Fold-change: 9.31E-02
Z-score: 4.63E+00
Experimental Note Discovered Using In-vivo Testing Model
Experiment for
Molecule Alteration		 Efflux pump genes expression analysis
Mechanism Description Ketorolac-fluconazole in vitro combination would be a promising strategy for further clinical in vivo trials to overcome fluconazole resistance in AML patients on induction chemotherapy. To our knowledge, the current study is the first in vitro report on the use of ketorolac in reverting fluconazole resistance in C. albicans isolated from AML patients. Resistance of C. albicans to azole antifungals is associated with overexpression of efflux pump genes especially CDR1 and MDR1.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa_circ_0001946 [2]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Ketorolac
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
Experiment for
Molecule Alteration		 Efflux pump genes expression analysis
Mechanism Description Ketorolac-fluconazole in vitro combination would be a promising strategy for further clinical in vivo trials to overcome fluconazole resistance in AML patients on induction chemotherapy. To our knowledge, the current study is the first in vitro report on the use of ketorolac in reverting fluconazole resistance in C. albicans isolated from AML patients. Resistance of C. albicans to azole antifungals is associated with overexpression of efflux pump genes especially CDR1 and MDR1.
Doxorubicin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Hexokinase-2 (HK2) [5]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myelocytic leukemia
The Studied Tissue Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.29E-13
Fold-change: 1.01E-01
Z-score: 7.67E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell viability Activation hsa05200
miR125a/hexokinase 2 pathway Regulation N.A.
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Hk2, a target of miR-125a, was positively regulated by uca1 in HL60, and HL60/ADR cells,and UCA1 overexpression significantly attenuated miR-125-mediated inhibition on HIF-1alpha-dependent glycolysis in HL60 and HL60/ADR cells.
Key Molecule: Protein S100-A4 (S100A4) [29]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
miR520c-3p/S100A4 signaling pathway Regulation N.A.
In Vitro Model THP-1 cells Blood Homo sapiens (Human) CVCL_0006
U937 cells Blood Homo sapiens (Human) CVCL_0007
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR; Luciferase reporter assay
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description HOXA-AS2 Can enhance S100A4 expression by suppressing miR-520c-3p expression to promote adriamycin resistance in acute myeloid leukemia through the miR-520c-3p /S100A4 pathway.
Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [30]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Experiment for
Molecule Alteration		 Western blot analysis; RT-qPCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis.
Key Molecule: RAC serine/threonine-protein kinase (AKT) [31]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Phosphorylation
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell colony Activation hsa05200
Cell invasion Activation hsa05200
Cell viability Activation hsa05200
PI3K/AKT/mTOR signaling pathway Activation hsa04151
In Vitro Model KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; TUNEL assay; Flow cytometry assay
Mechanism Description Long non coding RNA linc00239 promotes malignant behaviors and chemoresistance against doxorubicin partially via activation of the PI3k/Akt/mTOR pathway in acute myeloid leukaemia cells.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-34 [28]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
HS-5 cells Bone marrow Homo sapiens (Human) CVCL_3720
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description TUG1 epigenetically suppressed miR-34a expression by recruiting EZH2 to the promoter region of miR-34a and increasing H3k27me3 level to confer adriamycin resistance in acute myeloid leukemia.
Key Molecule: Taurine up-regulated 1 (TUG1) [28]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
HS-5 cells Bone marrow Homo sapiens (Human) CVCL_3720
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description TUG1 epigenetically suppressed miR-34a expression by recruiting EZH2 to the promoter region of miR-34a and increasing H3k27me3 level to confer adriamycin resistance in acute myeloid leukemia.
Key Molecule: hsa-miR-520c-3p [29]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
miR520c-3p/S100A4 signaling pathway Regulation N.A.
In Vitro Model THP-1 cells Blood Homo sapiens (Human) CVCL_0006
U937 cells Blood Homo sapiens (Human) CVCL_0007
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description HOXA-AS2 Can enhance S100A4 expression by suppressing miR-520c-3p expression to promote adriamycin resistance in acute myeloid leukemia through the miR-520c-3p /S100A4 pathway.
Key Molecule: HOXA cluster antisense RNA 2 (HOXA-AS2) [29]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
miR520c-3p/S100A4 signaling pathway Regulation N.A.
In Vitro Model THP-1 cells Blood Homo sapiens (Human) CVCL_0006
U937 cells Blood Homo sapiens (Human) CVCL_0007
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description HOXA-AS2 Can enhance S100A4 expression by suppressing miR-520c-3p expression to promote adriamycin resistance in acute myeloid leukemia through the miR-520c-3p /S100A4 pathway.
Key Molecule: hsa-miR-153-5p [30]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis.
Key Molecule: hsa-miR-183-5p [30]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis.
Key Molecule: Long non-protein coding RNA 239 (LINC00239) [31]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell colony Activation hsa05200
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
Cell viability Activation hsa05200
PI3K/AKT/mTOR signaling pathway Activation hsa04151
In Vitro Model KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; TUNEL assay; Flow cytometry assay
Mechanism Description Long non coding RNA linc00239 promotes malignant behaviors and chemoresistance against doxorubicin partially via activation of the PI3k/Akt/mTOR pathway in acute myeloid leukaemia cells.
Key Molecule: Urothelial cancer associated 1 (UCA1) [5]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell viability Activation hsa05200
miR125a/hexokinase 2 pathway Regulation N.A.
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Hk2, a target of miR-125a, was positively regulated by uca1 in HL60, and HL60/ADR cells,and UCA1 overexpression significantly attenuated miR-125-mediated inhibition on HIF-1alpha-dependent glycolysis in HL60 and HL60/ADR cells.
Key Molecule: hsa-mir-125b [32]
Resistant Disease Acute promyelocytic leukemia [ICD-11: 2A60.2]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
NB4 cells Bone marrow Homo sapiens (Human) CVCL_0005
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-125b could promote leukemic cell proliferation and inhibit cell apoptosis by regulating the expression of tumor suppressor BCL2-antagonist/killer 1 (Bak1). transfection of a miR-125b duplex into AML cells can increase their resistance to therapeutic drugs.
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Rho associated coiled-coil containing protein kinase 2 (ROCK2) [33]
Metabolic Type Glucose metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MAPK signaling pathway Activation hsa04010
PI3K-Akt signaling pathway Activation hsa04151
In Vitro Model HL-60/ADM cells Blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In this study, we found that there was a pronounced upregulation of ROCK2 in AML cells. Suppressing ROCK2 significantly boosts the effectiveness of drugs in both AML cell lines and primary AML specimens while causing a substantial decrease in the activation of MAPK and PI3K/AKT pathways.
Key Molecule: Carbonic anhydrase 13 (CA13) [34]
Metabolic Type Lipid metabolism
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HL-60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
THP1 cells Pleural effusion Homo sapiens (Human) CVCL_0006
Experiment for
Drug Resistance		 IC50 assay
Mechanism Description CA13is involved in cellular pH regulation, carbon dioxide transport, and cell homeostasis. Abnormalities in these processes can affect the tumor microenvironment, influencing cancer cell survival, proliferation, and resistance to therapy
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase KRas (KRAS) [6]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myelocytic leukemia
The Studied Tissue Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 9.27E-01
Fold-change: -7.42E-04
Z-score: -9.16E-02
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 Dual luciferase reporter assay; Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Flow cytometric analysis
Mechanism Description microRNA 217 inhibits cell proliferation and enhances chemosensitivity to doxorubicin in acute myeloid leukemia by targeting kRAS.
Key Molecule: Hexokinase-2 (HK2) [5]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell viability Inhibition hsa05200
miR125a/hexokinase 2 pathway Regulation N.A.
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Hk2, a target of miR-125a, was positively regulated by uca1 in HL60, and HL60/ADR cells,and UCA1 overexpression significantly attenuated miR-125-mediated inhibition on HIF-1alpha-dependent glycolysis in HL60 and HL60/ADR cells.
Key Molecule: High mobility group protein B1 (HMGB1) [7]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell migration Inhibition hsa04670
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.
Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [7]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell migration Inhibition hsa04670
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa_circ_PAN3 [30]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
In Vitro Model THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis.
Key Molecule: hsa-miR-153-5p [30]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
In Vitro Model THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis.
Key Molecule: hsa-miR-183-5p [30]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
In Vitro Model THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis.
Key Molecule: hsa-mir-217 [6]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell proliferation Inhibition hsa05200
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometric analysis
Mechanism Description microRNA 217 inhibits cell proliferation and enhances chemosensitivity to doxorubicin in acute myeloid leukemia by targeting kRAS.
Key Molecule: Urothelial cancer associated 1 (UCA1) [5]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell viability Inhibition hsa05200
miR125a/hexokinase 2 pathway Regulation N.A.
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Hk2, a target of miR-125a, was positively regulated by uca1 in HL60, and HL60/ADR cells,and UCA1 overexpression significantly attenuated miR-125-mediated inhibition on HIF-1alpha-dependent glycolysis in HL60 and HL60/ADR cells.
Key Molecule: hsa-mir-181 [7]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell migration Inhibition hsa04670
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description The ectopic expression of miR-181b in k562/A02 and HL-60/ADM cells robustly suppressed endogenous HMGB1 and Mcl-1 expression both at mRNA and protein levels. Conversely, knockdown of miR-181b by miR-181b inhibitor markedly increased the expression of both HMGB1 and Mcl-1. Restoration of miR-181b increased the drug sensitivity of AML MDR cells by targeting HMGB1 and Mcl-1.
Daunorubicin
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Eukaryotic translation initiation factor 5A-2 (EIF5A2) [9]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Daunorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myelocytic leukemia
The Studied Tissue Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 3.74E-03
Fold-change: -4.62E-02
Z-score: -2.92E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
Cell viability Inhibition hsa05200
In Vitro Model KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; EdU assay; Flow cytometry assay
Mechanism Description miR-9 improved the anti-tumor effects of Dnr by inhibiting myeloid cell leukemia-1 (MCL-1) expression, which was dependent on downregulation of EIF5A2 expression.
Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [25]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Daunorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Experiment for
Molecule Alteration		 Western blot analysis; RT-qPCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description MCL-1 participates in the regulation of DNR sensitivity mediated by miR-33b and overexpression of miR-33b enhances DNR sensitivity by downregulating MCL-1 in AML cells.
Key Molecule: Eukaryotic translation initiation factor 5A-2 (EIF5A2) [25]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Daunorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Experiment for
Molecule Alteration		 Western blot analysis; RT-qPCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description microRNA-33b regulates sensitivity to daunorubicin in acute myelocytic leukemia by regulating eukaryotic translation initiation factor 5A-2.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-33b [25]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Daunorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description MCL-1 participates in the regulation of DNR sensitivity mediated by miR-33b and overexpression of miR-33b enhances DNR sensitivity by downregulating MCL-1 in AML cells.
Key Molecule: hsa-mir-9 [9]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Daunorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
Cell viability Inhibition hsa05200
In Vitro Model KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay; EdU assay; Flow cytometry assay
Mechanism Description miR-9 improved the anti-tumor effects of Dnr by inhibiting myeloid cell leukemia-1 (MCL-1) expression, which was dependent on downregulation of EIF5A2 expression.
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [23]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Daunorubicin
 Drug Info 
Molecule Alteration Missense mutation
p.R882H
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.40  Å
PDB: 6W8B
Mutant Type Structure Method: X-ray diffraction Resolution: 2.44  Å
PDB: 6W8J
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.46
TM score: 0.99493
Amino acid change:
R882H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
A
A
E
E
630
|
K
K
R
R
K
K
P
P
I
I
R
R
V
V
L
L
S
S
L
L
640
|
F
F
D
D
G
G
I
I
A
A
T
T
G
G
L
L
L
L
V
V
650
|
L
L
K
K
D
D
L
L
G
G
I
I
Q
Q
V
V
D
D
R
R
660
|
Y
Y
I
I
A
A
S
S
E
E
V
V
C
C
E
E
D
D
S
S
670
|
I
I
T
T
V
V
G
G
M
M
V
V
R
R
H
H
Q
Q
G
G
680
|
K
K
I
I
M
M
Y
Y
V
V
G
G
D
D
V
V
R
R
S
S
690
|
V
V
T
T
Q
Q
K
K
H
H
I
I
Q
Q
E
E
W
W
G
G
700
|
P
P
F
F
D
D
L
L
V
V
I
I
G
G
G
G
S
S
P
P
710
|
C
C
N
N
D
D
L
L
S
S
I
I
V
V
N
N
P
P
A
A
720
|
R
R
K
K
G
G
L
L
Y
Y
E
E
G
G
T
T
G
G
R
R
730
|
L
L
F
F
F
F
E
E
F
F
Y
Y
R
R
L
L
L
L
H
H
740
|
D
D
A
A
R
R
P
P
K
K
E
E
G
G
D
D
D
D
R
R
750
|
P
P
F
F
F
F
W
W
L
L
F
F
E
E
N
N
V
V
V
V
760
|
A
A
M
M
G
G
V
V
S
S
D
D
K
K
R
R
D
D
I
I
770
|
S
S
R
R
F
F
L
L
E
E
S
S
N
N
P
P
V
V
M
M
780
|
I
I
D
D
A
A
K
K
E
E
V
V
S
S
A
A
A
A
H
H
790
|
R
R
A
A
R
R
Y
Y
F
F
W
W
G
G
N
N
L
L
P
P
800
|
G
G
M
M
N
N
R
R
P
P
L
L
A
A
S
S
T
T
V
V
810
|
N
N
D
D
K
K
L
L
E
E
L
L
Q
Q
E
E
C
C
L
L
820
|
E
E
H
H
G
G
R
R
I
I
A
A
K
K
F
F
S
S
K
K
830
|
V
V
R
R
T
T
I
I
T
T
T
T
R
R
S
S
N
N
S
S
840
|
I
I
K
K
Q
Q
G
G
K
K
D
D
Q
Q
H
H
F
F
P
P
850
|
V
V
F
F
M
M
N
N
E
E
K
K
E
E
D
D
I
I
L
L
860
|
W
W
C
C
T
T
E
E
M
M
E
E
R
R
V
V
F
F
G
G
870
|
F
F
P
P
V
V
H
H
Y
Y
T
T
D
D
V
V
S
S
N
N
880
|
M
M
S
S
R
H
L
L
A
A
R
R
Q
Q
R
R
L
L
L
L
890
|
G
G
R
R
S
S
W
W
S
S
V
V
P
P
V
V
I
I
R
R
900
|
H
H
L
L
F
F
A
A
P
P
L
L
K
K
E
E
Y
Y
F
F
910
|
A
A
C
C
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ADAM9/EGFR signaling pathway Inhibition hsa01521
AKT signaling pathway Inhibition hsa04151
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Mechanism Description DNMT3A mutations are most common in AML. DNMT3A mutant AML has been linked to anthracycline resistance and poor prognosis in some studies. Many of these mutations occur in genes with established roles in the regulation and maintenance of DNA methylation and/or chromatin modifications in hematopoietic stem/progenitor cells.
  Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: C-C motif chemokine 20 (CCL20) [24]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Daunorubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experiment for
Molecule Alteration		 ELISA assay
Mechanism Description Our study has identified CCL20 as a pivotal factor in the promotion of chemoresistance in AML cells by M2 macrophages. The chemotherapeutic agent daunorubicin induces a marked increase in ROS and lipid peroxidation levels within AML cells. This is accompanied by the inhibition of the SLC7A11/GCL/GPX4 signaling axis, elevated levels of intracellular free iron, disrupted iron metabolism, and consequent mitochondrial damage, ultimately leading to ferroptosis. Notably, CCL20 enhances the ability of AML cells to maintain iron homeostasis by upregulating SLC7A11 protein activity, mitigating mitochondrial damage, and inhibiting ferroptosis, thereby contributing to chemotherapy resistance. Furthermore, in vivo experiments demonstrated that blocking CCL20 effectively restores the sensitivity of AML cells to daunorubicin chemotherapy.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [10]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Daunorubicin
 Drug Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MAPK-RSKs-YB-1 signaling pathway Regulation N.A.
In Vitro Model MOLM-13 cells Peripheral blood Homo sapiens (Human) CVCL_2119
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
Experiment for
Drug Resistance		 Cell viability assay; Colony formation assay; Annexin-V/7-AAD double stain assay
Mechanism Description LJH-685 inhibited the proliferation and clone formation of AML cells, caused cell cycle arrest and induced the apoptosis of AML cells via inhibiting the RSK-YB-1 signaling pathway. MV4-11 and MOLM-13 cells carrying FLT3-ITD mutations were more sensitive to LJH-685 than that of other AML cell lines. Further studies suggested that LJH-685 combined with Daunorubicin or FF- 10101 synergistically inhibited the cell viability, promoted the apoptosis and caused cycle arrest of AML cells carrying FLT3-ITD mutations.
Arsenic trioxide
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-204 [12]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Arsenic trioxide
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cancer progression Inhibition hsa05200
In Vitro Model AML-5 cells Peripheral blood Homo sapiens (Human) CVCL_1620
HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description miR-204 decreases ATO chemoresistance in AML cells at least partially via promoting BIRC6/p53-mediated apoptosis.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Baculoviral IAP repeat-containing protein 6 (BIRC6) [12]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Arsenic trioxide
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation BIRC6/p53-mediated apoptosis signaling pathway Activation hsa04210
In Vitro Model AML-5 cells Peripheral blood Homo sapiens (Human) CVCL_1620
HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 Western blot analysis; RT-qPCR
Experiment for
Drug Resistance		 CCK8 assay; Flow cytometry assay
Mechanism Description miR-204 decreases ATO chemoresistance in AML cells at least partially via promoting BIRC6/p53-mediated apoptosis.
Avapritinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [13]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Avapritinib
 Drug Info 
Molecule Alteration Missense mutation
p.N822K (c.2466T>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
M-07e cells Peripheral blood Homo sapiens (Human) CVCL_2106
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
Chinese hamster ovary (CHO)-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Enzyme-linked immunosorbent assay; Cellular proliferation test assay
Cisplatin
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Cysteine and glycine-rich protein 1 (CSRP1) [14]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
Cell Pathway Regulation Rap1 signaling pathway Activation hsa04015
HIF-1 signaling pathway Activation hsa04066
JAK-STAT signaling pathway Activation hsa04630
In Vivo Model Patient-derived advanced AML model Homo sapiens
Experiment for
Drug Resistance		 OncoPredict assay
Mechanism Description Based on the findings, the high?CSRP1?groups of patients in the TCGA datasets showed higher sensitivity to 5-fluorouracil, gemcitabine, rapamycin, and cisplatin and lower sensitivity to fludarabine. CSRP1 may serve as a potential prognostic marker and a therapeutic target for AML in the future.
Dexamethasone
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: CREB-binding protein (CREBBP) [26], [27]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Dexamethasone
 Drug Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Exome sequencing assay; Transcriptome sequencing assay; Whole genome sequencing assay; Sanger Sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Several of these alterations are known to induce a more stem cell-like state (eg, IkZF1) or confer resistance directly to specific chemotherapy agents such as CREBBP and glucocorticoids and mutations in the 5-nucleotidase gene NT5C2 and nucleoside a.logs. Many relapse-acquired lesions are enriched in specific pathways, including B-cell development (IkZF1), tumor suppression (TP53),34 Ras signaling, chromatin modification (CREBBP, SETD2),17 and drug metabolism (NT5C2).
Fludarabine
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Cysteine and glycine-rich protein 1 (CSRP1) [14]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Fludarabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
Cell Pathway Regulation Rap1 signaling pathway Activation hsa04015
HIF-1 signaling pathway Activation hsa04066
JAK-STAT signaling pathway Activation hsa04630
In Vivo Model Patient-derived advanced AML model Homo sapiens
Experiment for
Drug Resistance		 OncoPredict assay
Mechanism Description Based on the findings, the high?CSRP1?groups of patients in the TCGA datasets showed higher sensitivity to 5-fluorouracil, gemcitabine, rapamycin, and cisplatin and lower sensitivity to fludarabine. CSRP1 may serve as a potential prognostic marker and a therapeutic target for AML in the future.
Fluorouracil
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Cysteine and glycine-rich protein 1 (CSRP1) [14]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Fluorouracil
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
Cell Pathway Regulation Rap1 signaling pathway Activation hsa04015
HIF-1 signaling pathway Activation hsa04066
JAK-STAT signaling pathway Activation hsa04630
In Vivo Model Patient-derived advanced AML model Homo sapiens
Experiment for
Drug Resistance		 OncoPredict assay
Mechanism Description Based on the findings, the high?CSRP1?groups of patients in the TCGA datasets showed higher sensitivity to 5-fluorouracil, gemcitabine, rapamycin, and cisplatin and lower sensitivity to fludarabine. CSRP1 may serve as a potential prognostic marker and a therapeutic target for AML in the future.
Gemcitabine
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Cysteine and glycine-rich protein 1 (CSRP1) [14]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Gemcitabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
Cell Pathway Regulation Rap1 signaling pathway Activation hsa04015
HIF-1 signaling pathway Activation hsa04066
JAK-STAT signaling pathway Activation hsa04630
In Vivo Model Patient-derived advanced AML model Homo sapiens
Experiment for
Drug Resistance		 OncoPredict assay
Mechanism Description Based on the findings, the high?CSRP1?groups of patients in the TCGA datasets showed higher sensitivity to 5-fluorouracil, gemcitabine, rapamycin, and cisplatin and lower sensitivity to fludarabine. CSRP1 may serve as a potential prognostic marker and a therapeutic target for AML in the future.
Gemtuzumab ozogamicin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Myeloid cell surface antigen CD33 (CD33) [35]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Gemtuzumab ozogamicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
PI3K/AKT signaling pathway Activation hsa04151
In Vitro Model U937 cells Blood Homo sapiens (Human) CVCL_0007
KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
GDM-1 cells Blood Homo sapiens (Human) CVCL_1230
HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
NB4 cells Bone marrow Homo sapiens (Human) CVCL_0005
TF-1 cells Blood Homo sapiens (Human) CVCL_0559
Experiment for
Molecule Alteration		 Western Blot Analysis
Experiment for
Drug Resistance		 Flow cytometric SCNP assays
Mechanism Description AKT signaling modulates GO/calicheamicin-gamma1 cytotoxicity and is associated with cellular-resistance to these drugs. In turn, inhibition of AKT activation can greatly increase GO/calicheamicin-gamma1 sensitivity.
Gilteritinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Beclin-1 (BECN1) [36]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Gilteritinib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell autophagy Inhibition hsa04140
In Vitro Model MV4-11/Gilteritinib cells myeloid Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG132.
Key Molecule: Beclin-1 (BECN1) [36]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Gilteritinib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell autophagy Inhibition hsa04140
In Vitro Model MOLM-13/Gilteritinib cells myeloid Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG134.
Key Molecule: Microtubule-associated protein 1 light chain 3-II/I (LC3-II/LC3-I) [36]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Gilteritinib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell autophagy Inhibition hsa04140
In Vitro Model MV4-11/Gilteritinib cells myeloid Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG133.
Key Molecule: Microtubule-associated protein 1 light chain 3-II/I (LC3-II/LC3-I) [36]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Gilteritinib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell autophagy Inhibition hsa04140
In Vitro Model MOLM-13/Gilteritinib cells myeloid Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG135.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [37]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Gilteritinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
In Vivo Model Female NCr-nude mouse model Mus musculus
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Key Molecule: E3 ubiquitin-protein ligase RNF38 (RNF38) [36]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Gilteritinib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell autophagy Inhibition hsa04140
In Vitro Model MV4-11/Gilteritinib si-RNF38 cells myeloid Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay; qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG136.
Key Molecule: E3 ubiquitin-protein ligase RNF38 (RNF38) [36]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Gilteritinib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell autophagy Inhibition hsa04140
In Vitro Model MOLM-13/Gilteritinib si-RNF38 cells myeloid Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay; qRT-PCR
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG137.
Idarubicin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Cyclin-dependent kinase inhibitor 1A (CDKN1A) [19]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Idarubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation DNA Damage Response Mechanism Regulation N.A.
In Vitro Model MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM-13 cells Peripheral blood Homo sapiens (Human) CVCL_2119
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
TF-1 cells Blood Homo sapiens (Human) CVCL_0559
Experiment for
Molecule Alteration		 RT-qPCR; Western blot assay
Experiment for
Drug Resistance		 MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
Mechanism Description DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress.Using PCR arrays we observed an upregulation of of several DDR genes (CDKN1A, GADD45A, GADD45G, EXO1, and PPP1R15A) in KASUMI-1 and MV4-11 cell lines that survived following treatment with Idarubicin and Cytarabine.
Key Molecule: Acetyl-CoA acetyltransferase 2 (ACAT2) [19]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Idarubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation DNA Damage Response Mechanism Regulation N.A.
In Vitro Model MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM-13 cells Peripheral blood Homo sapiens (Human) CVCL_2119
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
TF-1 cells Blood Homo sapiens (Human) CVCL_0559
Experiment for
Molecule Alteration		 RT-qPCR; Western blot assay
Experiment for
Drug Resistance		 MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
Mechanism Description DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress. Especially, PPP1R15A is mainly involved in the recovery of the cells from stress and it was the only DDR gene upregulated in AML patients.
Key Molecule: Growth arrest and DNA damage-inducible protein GADD45 gamma (GADD45G) [19]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Idarubicin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation DNA Damage Response Mechanism Regulation N.A.
In Vitro Model MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM-13 cells Peripheral blood Homo sapiens (Human) CVCL_2119
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
TF-1 cells Blood Homo sapiens (Human) CVCL_0559
Experiment for
Molecule Alteration		 RT-qPCR; Western blot assay
Experiment for
Drug Resistance		 MTT assay; Trypan blue assay; Clonogenicity assay; IC50 assay; Flow cytometry assay
Mechanism Description DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress.Using PCR arrays we observed an upregulation of of several DDR genes (CDKN1A, GADD45A, GADD45G, EXO1, and PPP1R15A) in KASUMI-1 and MV4-11 cell lines that survived following treatment with Idarubicin and Cytarabine.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [38]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Idarubicin
 Drug Info 
Molecule Alteration Missense mutation
p.R882H (c.2645G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.40  Å
PDB: 6W8B
Mutant Type Structure Method: X-ray diffraction Resolution: 2.44  Å
PDB: 6W8J
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.46
TM score: 0.99493
Amino acid change:
R882H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
A
A
E
E
630
|
K
K
R
R
K
K
P
P
I
I
R
R
V
V
L
L
S
S
L
L
640
|
F
F
D
D
G
G
I
I
A
A
T
T
G
G
L
L
L
L
V
V
650
|
L
L
K
K
D
D
L
L
G
G
I
I
Q
Q
V
V
D
D
R
R
660
|
Y
Y
I
I
A
A
S
S
E
E
V
V
C
C
E
E
D
D
S
S
670
|
I
I
T
T
V
V
G
G
M
M
V
V
R
R
H
H
Q
Q
G
G
680
|
K
K
I
I
M
M
Y
Y
V
V
G
G
D
D
V
V
R
R
S
S
690
|
V
V
T
T
Q
Q
K
K
H
H
I
I
Q
Q
E
E
W
W
G
G
700
|
P
P
F
F
D
D
L
L
V
V
I
I
G
G
G
G
S
S
P
P
710
|
C
C
N
N
D
D
L
L
S
S
I
I
V
V
N
N
P
P
A
A
720
|
R
R
K
K
G
G
L
L
Y
Y
E
E
G
G
T
T
G
G
R
R
730
|
L
L
F
F
F
F
E
E
F
F
Y
Y
R
R
L
L
L
L
H
H
740
|
D
D
A
A
R
R
P
P
K
K
E
E
G
G
D
D
D
D
R
R
750
|
P
P
F
F
F
F
W
W
L
L
F
F
E
E
N
N
V
V
V
V
760
|
A
A
M
M
G
G
V
V
S
S
D
D
K
K
R
R
D
D
I
I
770
|
S
S
R
R
F
F
L
L
E
E
S
S
N
N
P
P
V
V
M
M
780
|
I
I
D
D
A
A
K
K
E
E
V
V
S
S
A
A
A
A
H
H
790
|
R
R
A
A
R
R
Y
Y
F
F
W
W
G
G
N
N
L
L
P
P
800
|
G
G
M
M
N
N
R
R
P
P
L
L
A
A
S
S
T
T
V
V
810
|
N
N
D
D
K
K
L
L
E
E
L
L
Q
Q
E
E
C
C
L
L
820
|
E
E
H
H
G
G
R
R
I
I
A
A
K
K
F
F
S
S
K
K
830
|
V
V
R
R
T
T
I
I
T
T
T
T
R
R
S
S
N
N
S
S
840
|
I
I
K
K
Q
Q
G
G
K
K
D
D
Q
Q
H
H
F
F
P
P
850
|
V
V
F
F
M
M
N
N
E
E
K
K
E
E
D
D
I
I
L
L
860
|
W
W
C
C
T
T
E
E
M
M
E
E
R
R
V
V
F
F
G
G
870
|
F
F
P
P
V
V
H
H
Y
Y
T
T
D
D
V
V
S
S
N
N
880
|
M
M
S
S
R
H
L
L
A
A
R
R
Q
Q
R
R
L
L
L
L
890
|
G
G
R
R
S
S
W
W
S
S
V
V
P
P
V
V
I
I
R
R
900
|
H
H
L
L
F
F
A
A
P
P
L
L
K
K
E
E
Y
Y
F
F
910
|
A
A
C
C
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow N.A.
In Vivo Model NOD/SCID mouse xenograft model Mus musculus
Mechanism Description The missense mutation p.R882H (c.2645G>A) in gene DNMT3A cause the sensitivity of Idarubicin by unusual activation of pro-survival pathway
Ivosidenib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [39]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Ivosidenib
 Drug Info 
Molecule Alteration Missense mutation
p.R132H (c.395G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.65  Å
PDB: 6BKX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.88  Å
PDB: 4UMX
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.46
TM score: 0.85834
Amino acid change:
R132H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
S
S
K
K
K
K
I
I
S
S
G
G
G
G
S
S
10
|
V
V
V
V
E
E
M
M
Q
Q
G
G
D
D
E
E
M
M
T
T
20
|
R
R
I
I
I
I
W
W
E
E
L
L
I
I
K
K
E
E
K
K
30
|
L
L
I
I
F
F
P
P
Y
Y
V
V
E
E
L
L
D
D
L
L
40
|
H
H
S
S
Y
Y
D
D
L
L
G
G
I
I
E
E
N
N
R
R
50
|
D
D
A
A
T
T
N
N
D
D
Q
Q
V
V
T
T
K
K
D
D
60
|
A
A
A
A
E
E
A
A
I
I
K
K
K
K
H
H
N
N
V
V
70
|
G
G
V
V
K
K
C
C
A
A
T
T
I
I
T
T
P
P
D
D
80
|
E
E
K
K
R
R
V
V
E
E
E
E
F
F
K
K
L
L
K
K
90
|
Q
Q
M
M
W
W
K
K
S
S
P
P
N
N
G
G
T
T
I
I
100
|
R
R
N
N
I
I
L
L
G
G
G
G
T
T
V
V
F
F
R
R
110
|
E
E
A
A
I
I
I
I
C
C
K
K
N
N
I
I
P
P
R
R
120
|
L
L
V
V
S
S
G
G
W
W
V
V
K
K
P
P
I
I
I
I
130
|
I
I
G
G
R
H
H
H
A
A
Y
Y
G
G
D
D
Q
Q
Y
Y
140
|
R
R
A
A
T
T
D
D
F
F
V
V
V
V
P
P
G
G
P
P
150
|
G
G
K
K
V
V
E
E
I
I
T
T
Y
Y
T
T
P
P
S
S
160
|
D
D
G
G
T
T
Q
Q
K
K
V
V
T
T
Y
Y
L
L
V
V
170
|
H
H
N
N
F
F
E
E
E
E
G
G
G
G
G
G
V
V
A
A
180
|
M
M
G
G
M
M
Y
Y
N
N
Q
Q
D
D
K
K
S
S
I
I
190
|
E
E
D
D
F
F
A
A
H
H
S
S
S
S
F
F
Q
Q
M
M
200
|
A
A
L
L
S
S
K
K
G
G
W
W
P
P
L
L
Y
Y
L
L
210
|
S
S
T
T
K
K
N
N
T
T
I
I
L
L
K
K
K
K
Y
Y
220
|
D
D
G
G
R
R
F
F
K
K
D
D
I
I
F
F
Q
Q
E
E
230
|
I
I
Y
Y
D
D
K
K
Q
Q
Y
Y
K
K
S
S
Q
Q
F
F
240
|
E
E
A
A
Q
Q
K
K
I
I
W
W
Y
Y
E
E
H
H
R
R
250
|
L
L
I
I
D
D
D
D
M
M
V
V
A
A
Q
Q
A
A
M
M
260
|
K
K
S
S
E
E
G
G
G
G
F
F
I
I
W
W
A
A
C
C
270
|
K
K
N
N
Y
Y
D
D
G
G
D
D
V
V
Q
Q
S
S
D
D
280
|
S
S
V
V
A
A
Q
Q
G
G
Y
Y
G
G
S
S
L
L
G
G
290
|
M
M
M
M
T
T
S
S
V
V
L
L
V
V
C
C
P
P
D
D
300
|
G
G
K
K
T
T
V
V
E
E
A
A
E
E
A
A
A
A
H
H
310
|
G
G
T
T
V
V
T
T
R
R
H
H
Y
Y
R
R
M
M
Y
Y
320
|
Q
Q
K
K
G
G
Q
Q
E
E
T
T
S
S
T
T
N
N
P
P
330
|
I
I
A
A
S
S
I
I
F
F
A
A
W
W
T
T
R
R
G
G
340
|
L
L
A
A
H
H
R
R
A
A
K
K
L
L
D
D
N
N
N
N
350
|
K
K
E
E
L
L
A
A
F
F
F
F
A
A
N
N
A
A
L
L
360
|
E
E
E
E
V
V
S
S
I
I
E
E
T
T
I
I
E
E
A
A
370
|
G
G
F
F
M
M
T
T
K
K
D
D
L
L
A
A
A
A
C
C
380
|
I
I
K
K
G
G
L
L
P
P
N
N
V
V
Q
Q
R
R
S
S
390
|
D
D
Y
Y
L
L
N
N
T
T
F
F
E
E
F
F
M
M
D
D
400
|
K
K
L
L
G
G
E
E
N
N
L
L
K
K
I
I
K
K
L
L
410
|
A
A
Q
Q
A
A
K
K
L
L
S
S
L
L
E
E
H
H
H
H
420
|
H
H
H
H
H
H
H
H
H
H
H
H
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [39]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Ivosidenib
 Drug Info 
Molecule Alteration Missense mutation
p.R132C (c.394C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.93  Å
PDB: 5GIR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6IO0
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.64
TM score: 0.30204
Amino acid change:
R132C
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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130
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140
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180
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190
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240
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [39]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Ivosidenib
 Drug Info 
Molecule Alteration Missense mutation
p.R132S (c.394C>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [39]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Ivosidenib
 Drug Info 
Molecule Alteration Missense mutation
p.R132G (c.394C>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [39]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Ivosidenib
 Drug Info 
Molecule Alteration Missense mutation
p.R132L (c.395G>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Lestaurtinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [40]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Lestaurtinib
 Drug Info 
Molecule Alteration Missense mutation
p.D835E
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow Blood Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Mechanism Description Among the mutational patterns underlying relapse, the authors detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TkD mutations) and the increased resistance to apoptosis (hyperactivation of TYk2). Moreover, FLT3/TkD and ITD being subclonal mutations is one of the plausible explanations of unsatisfying results of FLT3 inhibitors, along with many others concerning inadequate in vivo inhibition of the target, development of secondary pharmacokinetic or pharmacodynamic resistance, and influence of FLT3-mutant allelic burden.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [40]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Lestaurtinib
 Drug Info 
Molecule Alteration Chromosome variation
FLT3/ITD (Internal tandem duplication )
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow Blood Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Mechanism Description Among the mutational patterns underlying relapse, the authors detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TkD mutations) and the increased resistance to apoptosis (hyperactivation of TYk2). Moreover, FLT3/TkD and ITD being subclonal mutations is one of the plausible explanations of unsatisfying results of FLT3 inhibitors, along with many others concerning inadequate in vivo inhibition of the target, development of secondary pharmacokinetic or pharmacodynamic resistance, and influence of FLT3-mutant allelic burden.
Mercaptopurine
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [27], [41]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Mercaptopurine
 Drug Info 
Molecule Alteration Missense mutation
p.R238W (c.c712t)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5OPP
Mutant Type Structure Method: X-ray diffraction Resolution: 1.84  Å
PDB: 5L4Z
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.41
TM score: 0.99758
Amino acid change:
R238W
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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140
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160
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C
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230
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240
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D
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260
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M
M
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T
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G
270
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P
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K
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S
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H
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P
W
W
280
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D
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I
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L
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D
D
290
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A
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E
G
G
300
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D
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T
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K
T
T
310
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G
G
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K
L
L
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K
I
I
G
G
T
T
Y
Y
T
T
G
G
320
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P
P
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L
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Q
H
H
G
G
I
I
V
V
Y
Y
S
S
G
G
330
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G
G
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S
S
S
D
D
T
T
I
I
C
C
D
D
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L
L
L
340
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G
G
A
A
K
K
G
G
K
K
D
D
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L
Y
Y
I
I
350
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G
G
D
D
H
H
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I
F
F
G
G
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D
I
I
L
L
K
K
360
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S
S
K
K
K
K
R
R
Q
Q
G
G
W
W
R
R
T
T
F
F
370
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L
L
V
V
I
I
P
P
E
E
L
L
A
A
Q
Q
E
E
L
L
380
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H
H
V
V
W
W
T
T
D
D
K
K
S
S
S
S
L
L
F
F
390
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E
E
E
E
L
L
Q
Q
S
S
L
L
D
D
I
I
F
F
L
L
400
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A
A
E
E
L
L
Y
Y
K
K
H
H
L
L
D
D
S
S
S
S
410
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S
S
N
N
E
E
R
R
P
P
D
D
I
I
S
S
S
S
I
I
420
|
Q
Q
R
R
R
R
I
I
K
K
K
K
V
V
T
T
H
H
D
D
430
|
M
M
D
D
M
M
C
C
Y
Y
G
G
M
M
M
M
G
G
S
S
440
|
L
L
F
F
R
R
S
S
G
G
S
S
R
R
Q
Q
T
T
L
L
450
|
F
F
A
A
S
S
Q
Q
V
V
M
M
R
R
Y
Y
A
A
D
D
460
|
L
L
Y
Y
A
A
A
A
S
S
F
F
I
I
N
N
L
L
L
L
470
|
Y
Y
Y
Y
P
P
F
F
S
S
Y
Y
L
L
F
F
R
R
A
A
480
|
A
A
H
H
V
V
L
L
M
M
P
P
H
H
E
E
S
S
-
T
490
|
-
V
-
E
-
H
-
T
-
H
-
V
-
D
-
I
-
N
-
E
500
|
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M
-
E
-
S
-
P
-
L
-
A
-
T
-
R
-
N
-
R
510
|
-
T
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S
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D
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F
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K
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T
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D
-
Y
520
|
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K
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R
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H
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Q
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R
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S
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I
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S
530
|
-
E
-
I
-
K
-
P
-
P
-
N
-
L
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Exome sequencing assay; Transcriptome sequencing assay; Whole genome sequencing assay; Sanger Sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Several of these alterations are known to induce a more stem cell-like state (eg, IkZF1) or confer resistance directly to specific chemotherapy agents such as CREBBP and glucocorticoids and mutations in the 5-nucleotidase gene NT5C2 and nucleoside a.logs. Many relapse-acquired lesions are enriched in specific pathways, including B-cell development (IkZF1), tumor suppression (TP53),34 Ras signaling, chromatin modification (CREBBP, SETD2),17 and drug metabolism (NT5C2).
Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [27], [41]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Mercaptopurine
 Drug Info 
Molecule Alteration Missense mutation
p.S445F (c.c1334t)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Exome sequencing assay; Transcriptome sequencing assay; Whole genome sequencing assay; Sanger Sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Several of these alterations are known to induce a more stem cell-like state (eg, IkZF1) or confer resistance directly to specific chemotherapy agents such as CREBBP and glucocorticoids and mutations in the 5-nucleotidase gene NT5C2 and nucleoside a.logs. Many relapse-acquired lesions are enriched in specific pathways, including B-cell development (IkZF1), tumor suppression (TP53),34 Ras signaling, chromatin modification (CREBBP, SETD2),17 and drug metabolism (NT5C2).
Metformin
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: Integrin beta-1 (ITGB1) [11]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Metformin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model KG-1 A cells Blood Homo sapiens (Human) CVCL_0374
Experiment for
Molecule Alteration		 qPCR; qRT-PCR
Experiment for
Drug Resistance		 Cell viability and proliferation assay; Cell cycle assay; Flow cytometric assay
Mechanism Description We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies.
Key Molecule: Platelet endothelial cell adhesion molecule (PECAM1) [11]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Metformin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model KG-1 A cells Blood Homo sapiens (Human) CVCL_0374
Experiment for
Molecule Alteration		 qPCR; qRT-PCR
Experiment for
Drug Resistance		 Cell viability and proliferation assay; Cell cycle assay; Flow cytometric assay
Mechanism Description We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies.
Key Molecule: Endoglin (ENG) [11]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Metformin
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model KG-1 A cells Blood Homo sapiens (Human) CVCL_0374
Experiment for
Molecule Alteration		 qPCR; qRT-PCR
Experiment for
Drug Resistance		 Cell viability and proliferation assay; Cell cycle assay; Flow cytometric assay
Mechanism Description We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies.
Key Molecule: CD9 antigen (CD9) [11]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Metformin
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model KG-1 A cells Blood Homo sapiens (Human) CVCL_0374
Experiment for
Molecule Alteration		 qPCR; qRT-PCR
Experiment for
Drug Resistance		 Cell viability and proliferation assay; Cell cycle assay; Flow cytometric assay
Mechanism Description We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies.
Midostaurin
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Ras-related C3 botulinum toxin substrate 1 (RAC1) [42]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Midostaurin
 Drug Info 
Molecule Alteration Function
Activation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
786-O cells Kidney Homo sapiens (Human) CVCL_1051
Experiment for
Molecule Alteration		 RAC1 activation assay
Experiment for
Drug Resistance		 CellTiter-Glo Luminescent Cell Viability Assay; Flow cytometric analysis
Mechanism Description Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD + AML.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [43]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.Y842C (c.2525A>G)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.Y842C (c.2525A>G) in gene FLT3 cause the sensitivity of Midostaurin by aberration of the drug's therapeutic target
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [44]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.D835Y (c.2503G>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow N.A.
Mechanism Description The missense mutation p.D835Y (c.2503G>T) in gene FLT3 cause the sensitivity of Midostaurin by aberration of the drug's therapeutic target
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [37]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
In Vivo Model Female NCr-nude mouse model Mus musculus
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [45]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.N822K (c.2466T>G)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) CVCL_0291
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Mitoxantrone
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-494 [46]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Mitoxantrone
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
U937 cells Blood Homo sapiens (Human) CVCL_0007
KG1a cells Pleural effusion Homo sapiens (Human) CVCL_1824
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description microRNA-494 activation suppresses bone marrow stromal cell-mediated drug resistance in acute myeloid leukemia cells.
Pexidartinib
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [47]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Pexidartinib
 Drug Info 
Molecule Alteration Missense mutation
p.D835Y
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MOLM-14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The pexidartinib IC50 values of cells with D835Y mutation was 206, the pexidartinib IC50 value of cells without mutation was 1.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [47]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Pexidartinib
 Drug Info 
Molecule Alteration Missense mutation
p.D835V
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MOLM-14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The pexidartinib IC50 values of cells with D835V mutation was 320, the pexidartinib IC50 value of cells without mutation was 1.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [47]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Pexidartinib
 Drug Info 
Molecule Alteration Missense mutation
p.D835I
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MOLM-14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The pexidartinib IC50 values of cells with D835I mutation was 1937, the pexidartinib IC50 value of cells without mutation was 1.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [47]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Pexidartinib
 Drug Info 
Molecule Alteration Missense mutation
p.D835F
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MOLM-14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The pexidartinib IC50 values of cells with D835F mutation was 415, the pexidartinib IC50 value of cells without mutation was 1.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [47]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Pexidartinib
 Drug Info 
Molecule Alteration Frameshift mutation
p.D835Del
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MOLM-14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The pexidartinib IC50 values of cells with D835Del mutation was 121, the pexidartinib IC50 value of cells without mutation was 1.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [47]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Pexidartinib
 Drug Info 
Molecule Alteration Missense mutation
p.F691L
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model MOLM-14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The multiple mutations that can confer resistance to quizartinib and pexidartinib. The gatekeeper mutation F691L was the most common mutation in all protocols involving quizartinib; it was rather frequent even with pexidartinib alone.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [47]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Pexidartinib
 Drug Info 
Molecule Alteration Missense mutation
p.F691L
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model MOLM-14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The multiple mutations that can confer resistance to quizartinib and pexidartinib. The gatekeeper mutation F691L was the most common mutation in all protocols involving quizartinib; it was rather frequent even with pexidartinib alone.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [47]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Pexidartinib
 Drug Info 
Molecule Alteration Missense mutation
p.F691L
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model U87-MG cells Brain Homo sapiens (Human) CVCL_0022
Ishikawa cells Endometrium Homo sapiens (Human) CVCL_2529
Mechanism Description The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib, but pexidartinib is much less resistance to this mutation. Pexidartinib alone is however sensitive to many other resistance mutations.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [47]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Pexidartinib
 Drug Info 
Molecule Alteration Missense mutation+Internal tandem duplication mutation
p.F691L+ FLT3-ITD
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model U87-MG cells Brain Homo sapiens (Human) CVCL_0022
Ishikawa cells Endometrium Homo sapiens (Human) CVCL_2529
Mechanism Description The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib, but pexidartinib is much less resistance to this mutation. Pexidartinib alone is however sensitive to many other resistance mutations.
Regorafenib
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [45]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.N822K (c.2466T>G)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) CVCL_0291
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Ripretinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [45]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Ripretinib
 Drug Info 
Molecule Alteration Missense mutation
p.N822K (c.2466T>G)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) CVCL_0291
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Ruxolitinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [48]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Ruxolitinib
 Drug Info 
Molecule Alteration Missense mutation
p.V617F (c.1849G>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow N.A.
Mechanism Description The missense mutation p.V617F (c.1849G>T) in gene JAK2 cause the sensitivity of Ruxolitinib by aberration of the drug's therapeutic target
Sirolimus
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Cysteine and glycine-rich protein 1 (CSRP1) [14]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Sirolimus
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
Cell Pathway Regulation Rap1 signaling pathway Activation hsa04015
HIF-1 signaling pathway Activation hsa04066
JAK-STAT signaling pathway Activation hsa04630
In Vivo Model Patient-derived advanced AML model Homo sapiens
Experiment for
Drug Resistance		 OncoPredict assay
Mechanism Description Based on the findings, the high?CSRP1?groups of patients in the TCGA datasets showed higher sensitivity to 5-fluorouracil, gemcitabine, rapamycin, and cisplatin and lower sensitivity to fludarabine. CSRP1 may serve as a potential prognostic marker and a therapeutic target for AML in the future.
Sorafenib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [49]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Sorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.F691
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
Experiment for
Drug Resistance		 Southern blot analysis; Spectral karyotyping assay
Mechanism Description FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [49]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Sorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.D835
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
Experiment for
Drug Resistance		 Southern blot analysis; Spectral karyotyping assay
Mechanism Description FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [50]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Sorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.D835Y
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 DNA sequencing assay
Experiment for
Drug Resistance		 Aldefluor activity analysis
Mechanism Description Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [50], [51]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Sorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.D835H
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 DNA sequencing assay
Experiment for
Drug Resistance		 Aldefluor activity analysis
Mechanism Description Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [51]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Sorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.F691L
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Deep amplicon sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description In this study, we report the clinical activity of sequential therapy with sorafenib and sunitinib in children with FLT3-ITD-positive AML and the emergence of polyclonal secondary FLT3 TkD mutations during TkI therapy as identified by deep amplicon sequencing.
Key Molecule: Tyrosine-protein kinase UFO (AXL) [52]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Sorafenib
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Axl signalling pathway Regulation N.A.
In Vitro Model MOLM-13/sor cells Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 Apoptosis assay
Mechanism Description Sorafenib-resistant MOLM-13/sor cells have increased protein levels of FLT3 and Axl signaling pathways. These results suggest that activated FLT3-ITD signaling, Axl signaling, and protein translation contribute to sorafenib resistance.
Key Molecule: Tyrosine-protein kinase receptor UFO (AXL) [52]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Sorafenib
 Drug Info 
Molecule Alteration Phosphorylation
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Axl signalling pathway Regulation N.A.
In Vitro Model MOLM-13/sor cells Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 Apoptosis assay
Mechanism Description Sorafenib-resistant MOLM-13/sor cells have increased protein levels of FLT3 and Axl signaling pathways. These results suggest that activated FLT3-ITD signaling, Axl signaling, and protein translation contribute to sorafenib resistance.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [52]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Sorafenib
 Drug Info 
Molecule Alteration Mutation
D1194A
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation FLT3-ITD signalling pathway Regulation N.A.
In Vitro Model MOLM-13/sor cells Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 WES assay
Experiment for
Drug Resistance		 Apoptosis assay
Mechanism Description Sorafenib-resistant MOLM-13/sor cells have increased protein levels of FLT3 and Axl signaling pathways. These results suggest that activated FLT3-ITD signaling, Axl signaling, and protein translation contribute to sorafenib resistance.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [52]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Sorafenib
 Drug Info 
Molecule Alteration Mutation
Rv1173; c.-32 A?>?G
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation FLT3-ITD signalling pathway Regulation N.A.
In Vitro Model MOLM-13/sor cells Blood Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 WES assay
Experiment for
Drug Resistance		 Apoptosis assay
Mechanism Description Sorafenib-resistant MOLM-13/sor cells have increased protein levels of FLT3 and Axl signaling pathways. These results suggest that activated FLT3-ITD signaling, Axl signaling, and protein translation contribute to sorafenib resistance.
Sunitinib
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [51]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Sunitinib
 Drug Info 
Molecule Alteration Missense mutation
p.D835Y
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Deep amplicon sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description In this study, we report the clinical activity of sequential therapy with sorafenib and sunitinib in children with FLT3-ITD-positive AML and the emergence of polyclonal secondary FLT3 TkD mutations during TkI therapy as identified by deep amplicon sequencing.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [49]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Sunitinib
 Drug Info 
Molecule Alteration Missense mutation
p.F691
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
Experiment for
Drug Resistance		 Southern blot analysis; Spectral karyotyping assay
Mechanism Description FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [49]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Sunitinib
 Drug Info 
Molecule Alteration Missense mutation
p.D835
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
Experiment for
Drug Resistance		 Southern blot analysis; Spectral karyotyping assay
Mechanism Description FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.
Tagraxofusp
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Diphthamide biosynthesis 1 (DPH1) [53]
Resistant Disease Blastic plasmacytoid dendritic cell neoplasm [ICD-11: 2A60.5]
Resistant Drug Tagraxofusp
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Jurkat cells Pleural effusion Homo sapiens (Human) CVCL_0065
SAOS-2 cells Bone marrow Homo sapiens (Human) CVCL_0548
MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
In Vivo Model NSG mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Loss of DPH1 is sufficient to confer relative tagraxofusp resistance in AML cells. CpGs further upstream, between -300 and -80 bases from the transcription start site (TSS), showed no significant change in methylation, suggesting that increased DPH1-promoter methylation associated with tagraxofusp resistance may confer a specific advantage. Given this finding, we hypothesized that azacitidine, a DNA methyltransferase inhibitor or DNA hypomethylating agent (HMA) might reverse resistance-associated DPH1 hypermethylation and restore DPH1 expression.
Tazemetostat
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [54]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Tazemetostat
 Drug Info 
Molecule Alteration Complex-indel
p.T678_R679delinsKK (c.2032_2037delinsAAGAAG)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model RN2c cells Blood Mus musculus (Mouse) N.A.
RN2 cells Blood Mus musculus (Mouse) N.A.
Plat-E cells Fetal kidney Homo sapiens (Human) CVCL_B488
Experiment for
Molecule Alteration		 RT-PCR
Thioguanine
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [27], [41]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Thioguanine
 Drug Info 
Molecule Alteration Missense mutation
p.R238W (c.c712t)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5OPP
Mutant Type Structure Method: X-ray diffraction Resolution: 1.84  Å
PDB: 5L4Z
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.41
TM score: 0.99758
Amino acid change:
R238W
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
G
-
S
-
S
-
H
-
H
-
H
-
H
-10
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-
H
-
H
-
S
-
S
-
G
-
L
-
V
-
P
-
R
-
G
0
|
-
S
-
M
-
S
T
T
S
S
W
W
S
S
D
D
R
R
L
L
10
|
Q
Q
N
N
A
A
A
A
D
D
M
M
P
P
A
A
N
N
M
M
20
|
D
D
K
K
H
H
A
A
L
L
K
K
K
K
Y
Y
R
R
R
R
30
|
E
E
A
A
Y
Y
H
H
R
R
V
V
F
F
V
V
N
N
R
R
40
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S
S
L
L
A
A
M
M
E
E
K
K
I
I
K
K
C
C
F
F
50
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G
G
F
F
D
D
M
M
D
D
Y
Y
T
T
L
L
A
A
V
V
60
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Y
Y
K
K
S
S
P
P
E
E
Y
Y
E
E
S
S
L
L
G
G
70
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F
F
E
E
L
L
T
T
V
V
E
E
R
R
L
L
V
V
S
S
80
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I
I
G
G
Y
Y
P
P
Q
Q
E
E
L
L
L
L
S
S
F
F
90
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A
A
Y
Y
D
D
S
S
T
T
F
F
P
P
T
T
R
R
G
G
100
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L
L
V
V
F
F
D
D
T
T
L
L
Y
Y
G
G
N
N
L
L
110
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L
L
K
K
V
V
D
D
A
A
Y
Y
G
G
N
N
L
L
L
L
120
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V
V
C
C
A
A
H
H
G
G
F
F
N
N
F
F
I
I
R
R
130
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G
G
P
P
E
E
T
T
R
R
E
E
Q
Q
Y
Y
P
P
N
N
140
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K
K
F
F
I
I
Q
Q
R
R
D
D
D
D
T
T
E
E
R
R
150
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F
F
Y
Y
I
I
L
L
N
N
T
T
L
L
F
F
N
N
L
L
160
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P
P
E
E
T
T
Y
Y
L
L
L
L
A
A
C
C
L
L
V
V
170
|
D
D
F
F
F
F
T
T
N
N
C
C
P
P
R
R
Y
Y
T
T
180
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S
S
C
C
E
E
T
T
G
G
F
F
K
K
D
D
G
G
D
D
190
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L
L
F
F
M
M
S
S
Y
Y
R
R
S
S
M
M
F
F
Q
Q
200
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D
D
V
V
R
R
D
D
A
A
V
V
D
D
W
W
V
V
H
H
210
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Y
Y
K
K
G
G
S
S
L
L
K
K
E
E
K
K
T
T
V
V
220
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E
E
N
N
L
L
E
E
K
K
Y
Y
V
V
V
V
K
K
D
D
230
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G
G
K
K
L
L
P
P
L
L
L
L
L
L
S
S
R
W
M
M
240
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K
K
E
E
V
V
G
G
K
K
V
V
F
F
L
L
A
A
T
T
250
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N
N
S
S
D
D
Y
Y
K
K
Y
Y
T
T
D
D
K
K
I
I
260
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M
M
T
T
Y
Y
L
L
F
F
D
D
F
F
P
P
H
H
G
G
270
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P
P
K
K
P
P
G
G
S
S
S
S
H
H
R
R
P
P
W
W
280
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Q
Q
S
S
Y
Y
F
F
D
D
L
L
I
I
L
L
V
V
D
D
290
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A
A
R
R
K
K
P
P
L
L
F
F
F
F
G
G
E
E
G
G
300
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T
T
V
V
L
L
R
R
Q
Q
V
V
D
D
T
T
K
K
T
T
310
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G
G
K
K
L
L
K
K
I
I
G
G
T
T
Y
Y
T
T
G
G
320
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P
P
L
L
Q
Q
H
H
G
G
I
I
V
V
Y
Y
S
S
G
G
330
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G
G
S
S
S
S
D
D
T
T
I
I
C
C
D
D
L
L
L
L
340
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G
G
A
A
K
K
G
G
K
K
D
D
I
I
L
L
Y
Y
I
I
350
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G
G
D
D
H
H
I
I
F
F
G
G
D
D
I
I
L
L
K
K
360
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S
S
K
K
K
K
R
R
Q
Q
G
G
W
W
R
R
T
T
F
F
370
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L
L
V
V
I
I
P
P
E
E
L
L
A
A
Q
Q
E
E
L
L
380
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H
H
V
V
W
W
T
T
D
D
K
K
S
S
S
S
L
L
F
F
390
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E
E
E
E
L
L
Q
Q
S
S
L
L
D
D
I
I
F
F
L
L
400
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A
A
E
E
L
L
Y
Y
K
K
H
H
L
L
D
D
S
S
S
S
410
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S
S
N
N
E
E
R
R
P
P
D
D
I
I
S
S
S
S
I
I
420
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Q
Q
R
R
R
R
I
I
K
K
K
K
V
V
T
T
H
H
D
D
430
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M
M
D
D
M
M
C
C
Y
Y
G
G
M
M
M
M
G
G
S
S
440
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L
L
F
F
R
R
S
S
G
G
S
S
R
R
Q
Q
T
T
L
L
450
|
F
F
A
A
S
S
Q
Q
V
V
M
M
R
R
Y
Y
A
A
D
D
460
|
L
L
Y
Y
A
A
A
A
S
S
F
F
I
I
N
N
L
L
L
L
470
|
Y
Y
Y
Y
P
P
F
F
S
S
Y
Y
L
L
F
F
R
R
A
A
480
|
A
A
H
H
V
V
L
L
M
M
P
P
H
H
E
E
S
S
-
T
490
|
-
V
-
E
-
H
-
T
-
H
-
V
-
D
-
I
-
N
-
E
500
|
-
M
-
E
-
S
-
P
-
L
-
A
-
T
-
R
-
N
-
R
510
|
-
T
-
S
-
V
-
D
-
F
-
K
-
D
-
T
-
D
-
Y
520
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-
K
-
R
-
H
-
Q
-
L
-
T
-
R
-
S
-
I
-
S
530
|
-
E
-
I
-
K
-
P
-
P
-
N
-
L
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Exome sequencing assay; Transcriptome sequencing assay; Whole genome sequencing assay; Sanger Sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Several of these alterations are known to induce a more stem cell-like state (eg, IkZF1) or confer resistance directly to specific chemotherapy agents such as CREBBP and glucocorticoids and mutations in the 5-nucleotidase gene NT5C2 and nucleoside a.logs. Many relapse-acquired lesions are enriched in specific pathways, including B-cell development (IkZF1), tumor suppression (TP53),34 Ras signaling, chromatin modification (CREBBP, SETD2),17 and drug metabolism (NT5C2).
Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [27], [41]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Thioguanine
 Drug Info 
Molecule Alteration Missense mutation
p.S445F (c.c1334t)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Next-generation sequencing assay; Exome sequencing assay; Transcriptome sequencing assay; Whole genome sequencing assay; Sanger Sequencing assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description Several of these alterations are known to induce a more stem cell-like state (eg, IkZF1) or confer resistance directly to specific chemotherapy agents such as CREBBP and glucocorticoids and mutations in the 5-nucleotidase gene NT5C2 and nucleoside a.logs. Many relapse-acquired lesions are enriched in specific pathways, including B-cell development (IkZF1), tumor suppression (TP53),34 Ras signaling, chromatin modification (CREBBP, SETD2),17 and drug metabolism (NT5C2).
Tretinoin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: ZBTB16-RARA fusion protein (ZBTB16-RARA) [55]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Tretinoin
 Drug Info 
Molecule Alteration Structural mutation
Structural variation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/PI3 signaling pathway Activation hsa04151
MAPK signaling pathway Activation hsa04010
STAT signaling pathway Activation hsa04630
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Mechanism Description However, rarer variant translocations such as t(11;17)(q23;q21); ZBTB16-RARA or t(17;17)(q21;q21); STAT5B-RARA may result in resistance to ATRA.
Key Molecule: STAT5B-RARA fusion protein (STAT5B-RARA) [55]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Tretinoin
 Drug Info 
Molecule Alteration Structural mutation
Structural variation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/PI3 signaling pathway Activation hsa04151
MAPK signaling pathway Activation hsa04010
STAT signaling pathway Activation hsa04630
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Mechanism Description However, rarer variant translocations such as t(11;17)(q23;q21); ZBTB16-RARA or t(17;17)(q21;q21); STAT5B-RARA may result in resistance to ATRA.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: t(17;17)(q21;q21) (Unclear) [55]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Tretinoin
 Drug Info 
Molecule Alteration Structural mutation
Structural variation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/PI3 signaling pathway Activation hsa04151
MAPK signaling pathway Activation hsa04010
STAT signaling pathway Activation hsa04630
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Mechanism Description However, rarer variant translocations such as t(11;17)(q23;q21); ZBTB16-RARA or t(17;17)(q21;q21); STAT5B-RARA may result in resistance to ATRA.
Key Molecule: t(11;17)(q23;q21) (Unclear) [55]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Resistant Drug Tretinoin
 Drug Info 
Molecule Alteration Structural mutation
Structural variation
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation AKT/PI3 signaling pathway Activation hsa04151
MAPK signaling pathway Activation hsa04010
STAT signaling pathway Activation hsa04630
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Mechanism Description However, rarer variant translocations such as t(11;17)(q23;q21); ZBTB16-RARA or t(17;17)(q21;q21); STAT5B-RARA may result in resistance to ATRA.
Clinical Trial Drug(s)
3 drug(s) in total
Click to Show/Hide the Full List of Drugs
Trichostatin A
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Endoplasmic reticulum chaperone BiP (HSPA5) [4]
Resistant Disease Adult acute myeloid leukemia [ICD-11: 2A60.1]
Resistant Drug Trichostatin A
 Drug Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myelocytic leukemia
The Studied Tissue Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 7.36E-14
Fold-change: 6.88E-02
Z-score: 7.87E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description GRP78 up-regulation is a major contributor to tumorigenesis and therapeutic resistance, miR-30d, miR-181a and miR-199a-5p regulate GRP78 and that their decreased expression in tumor cells results in increased GRP78 levels, which in turn promotes tumorigenesis and therapeutic resistance.
TRAIL
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Zinc finger protein PLAG1 (PLAG1) [8]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug TRAIL
 Drug Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Acute myeloid leukemia [ICD-11: 2A60]
The Specified Disease Acute myelocytic leukemia
The Studied Tissue Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.54E-01
Fold-change: -2.99E-02
Z-score: -1.43E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
In Vitro Model HL60 cells Peripheral blood Homo sapiens (Human) CVCL_0002
K562 cells Blood Homo sapiens (Human) CVCL_0004
K562/A02 cells Blood Homo sapiens (Human) CVCL_0368
NB4 cells Bone marrow Homo sapiens (Human) CVCL_0005
HL-60/ADR cells Blood Homo sapiens (Human) CVCL_0304
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-424 and miR-27a increase TRAIL sensitivity of acute myeloid leukemia by targeting PLAG1.
Crenolanib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [56]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Crenolanib
 Drug Info 
Molecule Alteration Missense mutation
p.D835H (c.2503G>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Colony assays; Plasma inhibitory assay
Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [37]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
Sensitive Drug Crenolanib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
In Vivo Model Female NCr-nude mouse model Mus musculus
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
References
Ref 1 The roles and mechanisms of TGFB1 in acute myeloid leukemia chemoresistance. Cell Signal. 2024 Apr;116:111027.
Ref 2 Ketorolac-fluconazole: A New Combination Reverting Resistance in Candida albicans from Acute Myeloid Leukemia Patients on Induction Chemotherapy: In vitro Study .J Blood Med. 2021 Jun 15;12:465-474. doi: 10.2147/JBM.S302158. eCollection 2021. 10.2147/JBM.S302158
Ref 3 Anti-miR-21 oligonucleotide enhances chemosensitivity of leukemic HL60 cells to arabinosylcytosine by inducing apoptosis. Hematology. 2010 Aug;15(4):215-21. doi: 10.1179/102453310X12647083620840.
Ref 4 miR-30d, miR-181a and miR-199a-5p cooperatively suppress the endoplasmic reticulum chaperone and signaling regulator GRP78 in cancer. Oncogene. 2013 Sep 26;32(39):4694-701. doi: 10.1038/onc.2012.483. Epub 2012 Oct 22.
Ref 5 Knockdown of LncRNA-UCA1 suppresses chemoresistance of pediatric AML by inhibiting glycolysis through the microRNA-125a/hexokinase 2 pathway. J Cell Biochem. 2018 Jul;119(7):6296-6308. doi: 10.1002/jcb.26899. Epub 2018 Apr 16.
Ref 6 MicroRNA 217 inhibits cell proliferation and enhances chemosensitivity to doxorubicin in acute myeloid leukemia by targeting KRAS. Oncol Lett. 2017 Jun;13(6):4986-4994. doi: 10.3892/ol.2017.6076. Epub 2017 Apr 24.
Ref 7 miR-181b increases drug sensitivity in acute myeloid leukemia via targeting HMGB1 and Mcl-1. Int J Oncol. 2014 Jul;45(1):383-92. doi: 10.3892/ijo.2014.2390. Epub 2014 Apr 16.
Ref 8 MiR-424 and miR-27a increase TRAIL sensitivity of acute myeloid leukemia by targeting PLAG1. Oncotarget. 2016 May 3;7(18):25276-90. doi: 10.18632/oncotarget.8252.
Ref 9 miR-9 Enhances the Chemosensitivity of AML Cells to Daunorubicin by Targeting the EIF5A2/MCL-1 Axis. Int J Biol Sci. 2019 Jan 1;15(3):579-586. doi: 10.7150/ijbs.29775. eCollection 2019.
Ref 10 Combination of RSK inhibitor LJH-685 and FLT3 inhibitor FF-10101 promoted apoptosis and proliferation inhibition of AML cell lines. Cell Oncol (Dordr). 2022 Oct;45(5):1005-1018.
Ref 11 Metformin as an Enhancer for the Treatment of Chemoresistant CD34+ Acute Myeloid Leukemia Cells. Genes (Basel). 2024 May 20;15(5):648.
Ref 12 MicroRNA-204 Potentiates the Sensitivity of Acute Myeloid Leukemia Cells to Arsenic Trioxide. Oncol Res. 2019 Sep 23;27(9):1035-1042. doi: 10.3727/096504019X15528367532612. Epub 2019 Apr 8.
Ref 13 A precision therapy against cancers driven by KIT/PDGFRA mutationsSci Transl Med. 2017 Nov 1;9(414):eaao1690. doi: 10.1126/scitranslmed.aao1690.
Ref 14 Cysteine- and glycine-rich protein 1 predicts prognosis and therapy response in patients with acute myeloid leukemia. Clin Exp Med. 2024 Mar 28;24(1):57.
Ref 15 Bone Marrow MicroRNA-335 Level Predicts the Chemotherapy Response and Prognosis of Adult Acute Myeloid Leukemia. Medicine (Baltimore). 2015 Aug;94(33):e0986. doi: 10.1097/MD.0000000000000986.
Ref 16 AHR signaling pathway mediates mitochondrial oxidative phosphorylation which leads to cytarabine resistance. Acta Biochim Biophys Sin (Shanghai). 2024 Apr 25;56(4):597-606.
Ref 17 Isocitrate dehydrogenase 2 mutation promotes cytarabine resistance in acute myeloid leukemia by Warburg effect. Hematol Oncol. 2024 Nov;42(6):e3316.
Ref 18 Isocitrate dehydrogenase 2 mutation promotes cytarabine resistance in acute myeloid leukemia by Warburg effect. Hematol Oncol. 2024 Nov;42(6):e3316.
Ref 19 Silencing of the DNA damage repair regulator PPP1R15A sensitizes acute myeloid leukemia cells to chemotherapy. Ann Hematol. 2024 Aug;103(8):2853-2863.
Ref 20 Upregulation of microRNA-126-5p is associated with drug resistance to cytarabine and poor prognosis in AML patients. Oncol Rep. 2015 May;33(5):2176-82. doi: 10.3892/or.2015.3839. Epub 2015 Mar 6.
Ref 21 CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia. J Clin Invest. 2013 Jun;123(6):2395-407. doi: 10.1172/JCI66553. Epub 2013 May 8.
Ref 22 MicroRNA-32 upregulation by 1,25-dihydroxyvitamin D3 in human myeloid leukemia cells leads to Bim targeting and inhibition of AraC-induced apoptosis. Cancer Res. 2011 Oct 1;71(19):6230-9. doi: 10.1158/0008-5472.CAN-11-1717. Epub 2011 Aug 4.
Ref 23 The role of mutations in epigenetic regulators in myeloid malignancies. Immunol Rev. 2015 Jan;263(1):22-35. doi: 10.1111/imr.12246.
Ref 24 M2 macrophages secrete CCL20 to regulate iron metabolism and promote daunorubicin resistance in AML cells. Life Sci. 2025 Jan 15;361:123297.
Ref 25 MicroRNA-33b regulates sensitivity to daunorubicin in acute myelocytic leukemia by regulating eukaryotic translation initiation factor 5A-2. J Cell Biochem. 2020 Jan;121(1):385-393. doi: 10.1002/jcb.29192. Epub 2019 Jun 21.
Ref 26 CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature. 2011 Mar 10;471(7337):235-9. doi: 10.1038/nature09727.
Ref 27 The genomic landscape of acute lymphoblastic leukemia in children and young adults. Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):174-80. doi: 10.1182/asheducation-2014.1.174. Epub 2014 Nov 18.
Ref 28 TUG1 confers Adriamycin resistance in acute myeloid leukemia by epigenetically suppressing miR-34a expression via EZH2. Biomed Pharmacother. 2019 Jan;109:1793-1801. doi: 10.1016/j.biopha.2018.11.003. Epub 2018 Nov 26.
Ref 29 Knockdown of Long Noncoding RNA HOXA-AS2 Suppresses Chemoresistance of Acute Myeloid Leukemia via the miR-520c-3p/S100A4 Axis. Cell Physiol Biochem. 2018;51(2):886-896. doi: 10.1159/000495387. Epub 2018 Nov 22.
Ref 30 CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis. Exp Hematol. 2019 Feb;70:42-54.e3. doi: 10.1016/j.exphem.2018.10.011. Epub 2018 Nov 3.
Ref 31 Long non coding RNA linc00239 promotes malignant behaviors and chemoresistance against doxorubicin partially via activation of the PI3K/Akt/mTOR pathway in acute myeloid leukaemia cells. Oncol Rep. 2019 Apr;41(4):2311-2320. doi: 10.3892/or.2019.6991. Epub 2019 Jan 31.
Ref 32 Upregulation of microRNA-125b contributes to leukemogenesis and increases drug resistance in pediatric acute promyelocytic leukemia. Mol Cancer. 2011 Sep 1;10:108. doi: 10.1186/1476-4598-10-108.
Ref 33 ROCK2 increases drug resistance in acute myeloid leukemia via metabolic reprogramming and MAPK/PI3K/AKT signaling. Int Immunopharmacol. 2024 Oct 25;140:112897.
Ref 34 Prognostic implications of metabolism-related genes in acute myeloid leukemia. Front Genet. 2024 Oct 3;15:1424365.
Ref 35 AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin PLoS One. 2013;8(1):e53518. doi: 10.1371/journal.pone.0053518. Epub 2013 Jan 8.
Ref 36 RNF38 promotes gilteritinib resistance in acute myeloid leukemia via inducing autophagy by regulating ubiquitination of LMX1A. Cell Biol Toxicol. 2024 Nov 28;40(1):105.
Ref 37 Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignanciesBr J Haematol. 2019 Nov;187(4):488-501. doi: 10.1111/bjh.16092. Epub 2019 Jul 15.
Ref 38 Do AML patients with DNMT3A exon 23 mutations benefit from idarubicin as compared to daunorubicin A single center experienceOncotarget. 2011 Nov;2(11):850-61. doi: 10.18632/oncotarget.347.
Ref 39 Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AMLN Engl J Med. 2018 Jun 21;378(25):2386-2398. doi: 10.1056/NEJMoa1716984. Epub 2018 Jun 2.
Ref 40 FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions. Mol Cancer Ther. 2017 Jun;16(6):991-1001. doi: 10.1158/1535-7163.MCT-16-0876.
Ref 41 Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia. Nat Genet. 2013 Mar;45(3):290-4. doi: 10.1038/ng.2558. Epub 2013 Feb 3.
Ref 42 Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia .Commun Biol. 2021 Jun 25;4(1):799. doi: 10.1038/s42003-021-02215-w. 10.1038/s42003-021-02215-w
Ref 43 Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML)Blood. 2005 Jan 1;105(1):335-40. doi: 10.1182/blood-2004-02-0660. Epub 2004 Sep 2.
Ref 44 Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3J Clin Oncol. 2010 Oct 1;28(28):4339-45. doi: 10.1200/JCO.2010.28.9678. Epub 2010 Aug 23.
Ref 45 Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA VariantsCancer Cell. 2019 May 13;35(5):738-751.e9. doi: 10.1016/j.ccell.2019.04.006.
Ref 46 MicroRNA-494 Activation Suppresses Bone Marrow Stromal Cell-Mediated Drug Resistance in Acute Myeloid Leukemia Cells. J Cell Physiol. 2017 Jun;232(6):1387-1395. doi: 10.1002/jcp.25628. Epub 2016 Oct 19.
Ref 47 Combating drug resistance in acute myeloid leukaemia by drug rotations: the effects of quizartinib and pexidartinib .Cancer Cell Int. 2021 Apr 8;21(1):198. doi: 10.1186/s12935-021-01856-5. 10.1186/s12935-021-01856-5
Ref 48 Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemiaBlood. 2012 May 17;119(20):4614-8. doi: 10.1182/blood-2011-12-400051. Epub 2012 Mar 15.
Ref 49 Mutation position within evolutionary subclonal architecture in AML. Semin Hematol. 2014 Oct;51(4):273-81. doi: 10.1053/j.seminhematol.2014.08.004. Epub 2014 Aug 7.
Ref 50 Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation. Blood. 2012 May 31;119(22):5133-43. doi: 10.1182/blood-2011-06-363960. Epub 2012 Feb 24.
Ref 51 Emergence of polyclonal FLT3 tyrosine kinase domain mutations during sequential therapy with sorafenib and sunitinib in FLT3-ITD-positive acute myeloid leukemia. Clin Cancer Res. 2013 Oct 15;19(20):5758-68. doi: 10.1158/1078-0432.CCR-13-1323. Epub 2013 Aug 22.
Ref 52 The GSK3beta/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors. Cell Death Discov. 2023 Feb 4;9(1):44.
Ref 53 DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance .J Clin Invest. 2019 Nov 1;129(11):5005-5019. doi: 10.1172/JCI128571. 10.1172/JCI128571
Ref 54 Rapid generation of drug-resistance alleles at endogenous loci using CRISPR-Cas9 indel mutagenesisPLoS One. 2017 Feb 23;12(2):e0172177. doi: 10.1371/journal.pone.0172177. eCollection 2017.
Ref 55 The diagnostic and clinical impact of genetics and epigenetics in acute myeloid leukemia. Int J Lab Hematol. 2015 May;37 Suppl 1:122-32. doi: 10.1111/ijlh.12367.
Ref 56 Crenolanib is a selective type I pan-FLT3 inhibitorProc Natl Acad Sci U S A. 2014 Apr 8;111(14):5319-24. doi: 10.1073/pnas.1320661111. Epub 2014 Mar 12.

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