Disease Information

General Information of the Disease (ID: DIS00502)

• Name: Acute myeloid leukemia
• ICD: ICD-11: 2A60

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Copanlisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Cyclin-dependent kinase 4 (CDK4) [1]

• Sensitive Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Sensitive Drug: Copanlisib
• Molecule Alteration: Expression; Express CDK4
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• Experiment for Molecule Alteration: Protein component assay; Immunoblotting assay; Immunofluorescence staining assay
• Experiment for Drug Resistance: Cell viability assay; Synergistic effects assay; Cell growth rates assay
• Mechanism Description: Considering the fact that for many tumour cells, inhibition of CDK4/6 can induce cellular quiescence or senescence, we evaluated whether CDK4 expression was affected by copanlisib alone or in combination with palbociclib. Copanlisib was selected as it was more effective than other PI3K inhibitors on its own. While the cells did not react to palbociclib by reducing the expression of CDK4, copanlisib lead to dose-dependent downregulation in CDK4 expression, especially when combined with palbociclib (Additional file 1: Fig. S8). Moreover, the cells did not express p-Akt following treatment with copanlisib (Additional file 1: Fig. S9).

Cytarabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Dihydrofolate reductase (DHFR) [2]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Cytarabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: THP1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate.

Key Molecule: Squalene synthase (FDFT1) [2]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Cytarabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: THP1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Dihydrofolate reductase (DHFR) [2]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: THP1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate.

Key Molecule: Squalene synthase (FDFT1) [2]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: THP1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0006
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate.

Tretinoin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Methyltransferase like 3 (METTL3) [3]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Tretinoin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: NB4 cells transfected with METTL3-OE were transplanted into BALB/C nude mice via subcutaneously inoculation; NB4 cells transfected with METTL3-OE were transplanted into BALB/C nude mice via tail vein injection; Mice
• Experiment for Molecule Alteration: Western blot analysis, qRT-PCR and CO-IP
• Experiment for Drug Resistance: Tumor images assay; Tumor volume assay; Tumor weight assay
• Mechanism Description: Histone lactylation and METTL3 expression levels were considerably upregulated in ATRA-resistant APL cells. METTL3 was regulated by histone lactylation and direct lactylation modification. Overexpression of METTL3 promoted ATRA-resistance. GRh2 ameliorated ATRA-resistance by downregulated lactylation level and directly inhibiting METTL3.

References

• Ref 1: Combination strategies to overcome drug resistance in FLT(+) acute myeloid leukaemia. Cancer Cell Int. 2023 Aug 11;23(1):161.
• Ref 2: Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy. Comput Struct Biotechnol J. 2021 Jul 8;19:4059-4066.
• Ref 3: 20(S)-ginsenoside Rh2 ameliorates ATRA resistance in APL by modulating lactylation-driven METTL3. J Ginseng Res. 2024 May;48(3):298-309.