Disease Information

General Information of the Disease (ID: DIS00060)

• Name: Acute lymphocytic leukemia
• ICD: ICD-11: 2B33

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

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 24 drug(s) in total

Arsenic trioxide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-21 [1]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Arsenic trioxide
• 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
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: PDCD4 has been reported to be involved in growth, apoptosis, invasion and cell cycle etc. AMO-miR-21 significantly sensitizes HL60 and k562 cells to ATO by inducing apoptosis, and these effects of AMO-miR-21 may be partially due to its up-regulation of PDCD4.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Programmed cell death protein 4 (PDCD4) [1]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Arsenic trioxide
• 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
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: PDCD4 has been reported to be involved in growth, apoptosis, invasion and cell cycle etc. AMO-miR-21 significantly sensitizes HL60 and k562 cells to ATO by inducing apoptosis, and these effects of AMO-miR-21 may be partially due to its up-regulation of PDCD4.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-153 [2]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Arsenic trioxide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Forced expression of miR-153 only in k562 cells has no significant effects on cell growth and apoptosis. However, when cells were additionally treated with As2O3, significant greater apoptosis was observed in the miR-153 overexpressed group.

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-138 [3]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• 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: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [3]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• 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 blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin.

Cladribine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Deoxycytidine kinase (DCK) [4]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cladribine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus strain; 1280
• Mechanism Description: Cladribine cannot be deaminated by adenosine deaminase(ADA) and is phosphorylated to cladribine-MP by dCK. Cladribine self potentiates its own activation by activation of dCK. The cytotoxicity mainly depends on the accumulation of cladribine-TP after phosphoryl-ation of cladribine-MP by nucleoside MP kinase and nucleoside diphosphate kinase in the cells. Down regulation of all activating enzymes such as dCK or dGK due to loss of expression or through mutation, has been shown to cause resistance to cladribine. However, the most frequently described form of acquired resistance to cladribine in vitro is dCK de ciency and reduction in dCK activity is probably the major determinant of cladribine resistance.

Key Molecule: Diacylglycerol kinase iota (DGKI) [4]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cladribine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus strain; 1280
• Mechanism Description: Cladribine cannot be deaminated by adenosine deaminase(ADA) and is phosphorylated to cladribine-MP by dCK. Cladribine self potentiates its own activation by activation of dCK. The cytotoxicity mainly depends on the accumulation of cladribine-TP after phosphoryl-ation of cladribine-MP by nucleoside MP kinase and nucleoside diphosphate kinase in the cells. Down regulation of all activating enzymes such as dCK or dGK due to loss of expression or through mutation, has been shown to cause resistance to cladribine. However, the most frequently described form of acquired resistance to cladribine in vitro is dCK de ciency and reduction in dCK activity is probably the major determinant of cladribine resistance.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Solute carrier family 29 member 1 (SLC29A1) [4]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cladribine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus strain; 1280
• Mechanism Description: Resistance of cytarabine resistant CEM cells to cladribine, among other purine and pyrimidine nucleoside drugs, was due to the absence of expression of the hENT1 gene leading to a loss ofnucleoside transport activity. Stable transfer of hCNT2 DNA into these resistant cells partially restored chemosensitivity for cladribine.

Cytarabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytidine deaminase (CDA) [5]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: Nalm-6 cells; Peripheral blood; Homo sapiens (Human); CVCL_0092
• Experiment for Molecule Alteration: Real-time quantitative PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Low-concentration cytarabine (Ara-C) continuously induced and cultured Jurkat and Nalm-6 cells to construct cytarabine-resistant cell lines Jurkat/Ara-C and Nalm-6/Ara-C. The results of real-time quantitative PCR showed that the expression of deoxycytidine kinase (DCk) and cytidine deaminase (CDA) were significantly down-regulated in drug-resistant cells (P<0.05).

Key Molecule: Deoxycytidine kinase (DCK) [5]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: Nalm-6 cells; Peripheral blood; Homo sapiens (Human); CVCL_0092
• Experiment for Molecule Alteration: Real-time quantitative PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Low-concentration cytarabine (Ara-C) continuously induced and cultured Jurkat and Nalm-6 cells to construct cytarabine-resistant cell lines Jurkat/Ara-C and Nalm-6/Ara-C. The results of real-time quantitative PCR showed that the expression of deoxycytidine kinase (DCk) and cytidine deaminase (CDA) were significantly down-regulated in drug-resistant cells (P<0.05).

Key Molecule: Cytidine deaminase (CDA) [6]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Also opposing the activation pathway are the two deaminase CDA and deoxycytidine monophosphate deaminase (dCMPD). Cytidine deaminase is a multi-subunit enzyme involved in the maintenance of the pyrimidine nucleotide pool within the cell and physiologically catalyzes the hydrolytic deamination of cytidine to uridine and deoxycytidine to deoxyuridine. In cytarabine biotransformation, CDA removes the amine group from its cytosine and converts the drug into the inactive uracil arabinoside derivative.

Key Molecule: Cardiolipin synthase (CLS) [6]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: CMPD deaminates cytarabine-monophosphate to arabinosyl-uracil-monophosphate. A crucial role for this latter enzyme has been suggested in the metabolism of cytarabine-monophosphate in T-lymphoblastic leukemia.

Key Molecule: Deoxycytidine kinase (DCK) [6]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Deoxycitidine kinase plays a pivotal role since phosphorylation of cytarabine preserves intracellular retention of the drug and prevents from inactivation to its uridine derivative, uracil arabinoside, by cytidine deaminase. The intracellular accumulation of cytarabine triphosphate, the active cytotoxic metabolite, is proportional to the cellular DCk level which has led to the conclusion that DCk enzyme retains a rate-limiting role for the activation of cytarabine.

Key Molecule: UMP-CMP kinase (CMPK1) [6]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Activation of cytarabine occurs by means of the step wise de novo synthesis of 5'-mono-, di-, and triphosphate derivatives throughout the sequential action of deoxycytidine kinase (DCk), deoxycytidine monophosphate kinase (dCMk), and nucleoside diphosphate kinase (NDk) encoded by the NME1 gene. Phosphorylated cytarabine metabolites interfere with the cellular pool of natural nucleosides, are incorporated into DNA and inhibit DNA synthesis in a competitive fashion. In vitro studies have revealed that the intracellular concentrations of cytarabine-triphosphate are higher in cytarabine sensitive cells than in resistant cells.

Key Molecule: Nucleoside diphosphate kinase A (NME1) [6]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Activation of cytarabine occurs by means of the step wise de novo synthesis of 5'-mono-, di-, and triphosphate derivatives throughout the sequential action of deoxycytidine kinase (DCk), deoxycytidine monophosphate kinase (dCMk), and nucleoside diphosphate kinase (NDk) encoded by the NME1 gene. Phosphorylated cytarabine metabolites interfere with the cellular pool of natural nucleosides, are incorporated into DNA and inhibit DNA synthesis in a competitive fashion. In vitro studies have revealed that the intracellular concentrations of cytarabine-triphosphate are higher in cytarabine sensitive cells than in resistant cells.

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [6]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Since monophosphorilated intermediate of cytarabine activation is reduced by cytosolic 5'-nucleotidases NT5C2 and NT5C3, the activity level of this enzyme may represent one of the factors affecting the clinical outcome of cytarabine therapy. Increased expression of NT5C2 has been correlated with resistance to cytarabine chemotherapy and to a lower survival rate in a hundred patients undergoing cytarabine chemotherapy. An increase in the NT5C2 has emerged as a mechanism of resistance to cytarabine. Patients with AML and low expression level of NT5C2 have a better overall survival after treatment with cytarabine than patients with high expression. NT5C2 is implicated in pharmacokinetic of cytarabine has been associated with poor clinical outcome.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family C10 (ABCC10) [6]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Uptake and accumulation of cytarabine is also regulated by transmembrane transporter proteins of the ABC family, also called human multidrug resistance-associated protein (MRP) family, namely ABCC10 (MRP7) and ABCC11 (MRP8) specifically committed to efflux of deoxynucleotides inactive metabolites and to temper intracellular pools of phosphorylated deoxynucleotides. The drug accumulation may be substantially reduced when the expression of hENT1 transporter is deficient, or the activity of ABC drug efflux transporter proteins is elevated.

Key Molecule: ATP-binding cassette sub-family C11(ABCC11) [6]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Uptake and accumulation of cytarabine is also regulated by transmembrane transporter proteins of the ABC family, also called human multidrug resistance-associated protein (MRP) family, namely ABCC10 (MRP7) and ABCC11 (MRP8) specifically committed to efflux of deoxynucleotides inactive metabolites and to temper intracellular pools of phosphorylated deoxynucleotides. The drug accumulation may be substantially reduced when the expression of hENT1 transporter is deficient, or the activity of ABC drug efflux transporter proteins is elevated.

Key Molecule: Solute carrier family 29 member 1 (SLC29A1) [6]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cytarabine
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Cytarabine gains entry into cells primarily as a false substrate through specialized nucleoside transporter proteins of SLC family, the human equilibrative nucleoside transportershENT1 and hENT2 (encoded by the gene SLC29A1 and SCL29A2, respectively) and the human concentrative nucleoside transporters hCNT3 (encoded by the gene SLC28A3). The drug accumulation may be substantially reduced when the expression of hENT1 transporter is deficient, or the activity of ABC drug efflux transporter proteins is elevated.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-181a [7]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cytarabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: HL-60/Ara-C-resistant cells; Blood; Homo sapiens (Human); CVCL_1736
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Bcl-2 was conWrmed as adirect miR-181a target by immunoblot analysis andreporter gene assays. knockdown of Bcl-2 mimicked theeVect of enforced miR-181a expression by reducing cellviability. In addition, the apoptosis pathway was activated by cytochrome C release and caspase 9/caspase 3 activationafter miR-181a overexpression. Down-regulation of miR-181a and upregulation of Bcl-2in leukaemia cells confer resistance to Ara-C-based ther-apy.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [7]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cytarabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: HL-60/Ara-C-resistant cells; Blood; Homo sapiens (Human); CVCL_1736
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Bcl-2 was conWrmed as adirect miR-181a target by immunoblot analysis andreporter gene assays. knockdown of Bcl-2 mimicked theeVect of enforced miR-181a expression by reducing cellviability. In addition, the apoptosis pathway was activated by cytochrome C release and caspase 9/caspase 3 activationafter miR-181a overexpression. Down-regulation of miR-181a and upregulation of Bcl-2in leukaemia cells confer resistance to Ara-C-based ther-apy.

Dasatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [8], [9]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.T315I
• Resistant Drug: Dasatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Drug Resistance: Flow cytometry assay; Analysis of disease free and overall survival assay
• Mechanism Description: Mutations were frequently detected at relapse. Among 17 patients analyzed, a T315I mutation was detected in 12, E255k in 1, and no BCR-ABL mutations in 4 (25886620). Thirteen relapsed patients had mutational analysis and 7 had ABL mutations (4 T315I, 1 F359V, and 2 V299L).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [8]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.E255K
• Resistant Drug: Dasatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Mutations were frequently detected at relapse. Among 17 patients analyzed, a T315I mutation was detected in 12, E255k in 1, and no BCR-ABL mutations in 4.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [9]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.V299L
• Resistant Drug: Dasatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Drug Resistance: Analysis of disease free and overall survival assay
• Mechanism Description: Thirteen relapsed patients had mutational analysis and 7 had ABL mutations (4 T315I, 1 F359V, and 2 V299L).

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [9]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.F359V
• Resistant Drug: Dasatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Drug Resistance: Analysis of disease free and overall survival assay
• Mechanism Description: Thirteen relapsed patients had mutational analysis and 7 had ABL mutations (4 T315I, 1 F359V, and 2 V299L).

Daunorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-125a [10]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Daunorubicin
• 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
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Luminescent cell viability assay
• Mechanism Description: miR125a mediated daunorubicin resistance in leukemia cell lines through the decrease of GRk2 and Puma which were proved to be direct targets of miR125a. Overexpression of miR125a induced drug resistance in HL-60, k562, and THP-1cell lines through reducing apoptosis.

Key Molecule: hsa-mir-125b [11]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Daunorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: REH cells; Bone marrow; Homo sapiens (Human); CVCL_1650
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Luminescent cell viability assay
• Mechanism Description: miR-125b downregulated GRk2 and PUMA, which inhibited apoptosis and induced leukemia cell resistance to DNR.

Key Molecule: hsa-mir-21 [12]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Daunorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562/DNR cells; Blood; Homo sapiens (Human); CVCL_4T87
• Experiment for Molecule Alteration: RT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: DNR-induced drug resistance is associated with upregulation of miR-21 in the leukaemia cell line k562. miR-21 may regulate the survival of leukaemia cell lines by targeting PTEN expression and causing subsequent changes in the PI3k/Akt pathway.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Beta adrenoceptor kinase 1 (GRK2) [10]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Daunorubicin
• 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
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: Luminescent cell viability assay
• Mechanism Description: miR125a mediated daunorubicin resistance in leukemia cell lines through the decrease of GRk2 and Puma which were proved to be direct targets of miR125a. Overexpression of miR125a induced drug resistance in HL-60, k562, and THP-1cell lines through reducing apoptosis.

Key Molecule: Bcl-2-binding component 3 (BBC3) [10]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Daunorubicin
• 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
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: Luminescent cell viability assay
• Mechanism Description: miR125a mediated daunorubicin resistance in leukemia cell lines through the decrease of GRk2 and Puma which were proved to be direct targets of miR125a. Overexpression of miR125a induced drug resistance in HL-60, k562, and THP-1cell lines through reducing apoptosis.

Key Molecule: Beta adrenoceptor kinase 1 (GRK2) [11]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Daunorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: REH cells; Bone marrow; Homo sapiens (Human); CVCL_1650
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Luminescent cell viability assay
• Mechanism Description: miR-125b downregulated GRk2 and PUMA, which inhibited apoptosis and induced leukemia cell resistance to DNR.

Key Molecule: Bcl-2-binding component 3 (BBC3) [11]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Daunorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: REH cells; Bone marrow; Homo sapiens (Human); CVCL_1650
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Luminescent cell viability assay
• Mechanism Description: miR-125b downregulated GRk2 and PUMA, which inhibited apoptosis and induced leukemia cell resistance to DNR.

Key Molecule: Phosphatase and tensin homolog (PTEN) [12]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Daunorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562/DNR cells; Blood; Homo sapiens (Human); CVCL_4T87
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: DNR-induced drug resistance is associated with upregulation of miR-21 in the leukaemia cell line k562. miR-21 may regulate the survival of leukaemia cell lines by targeting PTEN expression and causing subsequent changes in the PI3k/Akt pathway.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-210 [13]

• Sensitive Disease: Paediatric acute lymphocytic leukemia [ICD-11: 2B33.4]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Daunorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MLL/AF4+ RS4 cells; Blood; Homo sapiens (Human); CVCL_0093
• In Vitro Model: TEL/AML1+ Reh cells; Blood; Homo sapiens (Human); CVCL_ZV66
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: Functioning as a hypoxamir (i.e. a microRNA whose expression is upregulated by hypoxia), miR-210 targets many genes involved in a wide range of physiological processes, such as cell survival/proliferation, mitochondrial metabolism, protein modification/transport, DNA damage repair and angiogenesis. Increasing/decreasing miR-210 expression using agomir/antagomir could enhance or reduce the response of Reh cells and RS4;11 cells to daunorubicin/dexamethasone/L-asparaginase and daunorubicin/dexamethasone/vincristine, respectively. miR-210 may be a good prognostic factor and a useful predictor of drug sensitivity, and is a potential therapeutic target for pediatric ALL.

Key Molecule: hsa-mir-181a [14]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Daunorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562/A02 cells; Blood; Homo sapiens (Human); CVCL_0368
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Anti-apoptotic BCL-2 contributes to the survival and chemoresistance of quiescent leukemia CD34+ cells, leukemia cells with decreased miR-181a expression and elevated BCL-2 protein expression were more resistant to DNR than the control cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [14]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Daunorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562/A02 cells; Blood; Homo sapiens (Human); CVCL_0368
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Anti-apoptotic BCL-2 contributes to the survival and chemoresistance of quiescent leukemia CD34+ cells, leukemia cells with decreased miR-181a expression and elevated BCL-2 protein expression were more resistant to DNR than the control cells.

Dexamethasone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: CREB-binding protein (CREBBP) [15]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Dexamethasone
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Whole-genome sequencing assay
• Experiment for Drug Resistance: Flow cytometric analysis assay; MTT assay
• Mechanism Description: However, our analysis of protein-protein interaction networks of relapse-associated mutant factors supports that, at least in part, relapse-associated mutations may converge in common nodes related to escape from DNA damage response(TP53) and glucocorticoid resistance(CREBBP and NR3C1).

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: HOXA cluster antisense RNA 2 (HOXA-AS2) [16]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dexamethasone
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR/RAS/RAF/MEK/ERK signaling pathway; Activation; hsa01521
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: CCRF-CEM cells; Pleural effusion; Homo sapiens (Human); CVCL_0207
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: TCF7L2 activated HOXA-AS2 decreased the glucocorticoid sensitivity in acute lymphoblastic leukemia through regulating HOXA3/EGFR/Ras/Raf/MEk/ERk pathway.

Key Molecule: hsa-mir-124 [17]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dexamethasone
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: CCRF-CEM cells; Pleural effusion; Homo sapiens (Human); CVCL_0207
• In Vitro Model: CEM/C1 cells; Peripheral blood; Homo sapiens (Human); CVCL_3496
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR124 contributes to glucocorticoid resistance in acute lymphoblastic leukemia by promoting proliferation, inhibiting apoptosis and targeting NR3C1.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Homeobox protein Hox-A3 (HOXA3) [16]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dexamethasone
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR/RAS/RAF/MEK/ERK signaling pathway; Activation; hsa01521
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: CCRF-CEM cells; Pleural effusion; Homo sapiens (Human); CVCL_0207
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: TCF7L2 activated HOXA-AS2 decreased the glucocorticoid sensitivity in acute lymphoblastic leukemia through regulating HOXA3/EGFR/Ras/Raf/MEk/ERk pathway.

Key Molecule: Glucocorticoid receptor (NR3C1) [17]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Dexamethasone
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: CCRF-CEM cells; Pleural effusion; Homo sapiens (Human); CVCL_0207
• In Vitro Model: CEM/C1 cells; Peripheral blood; Homo sapiens (Human); CVCL_3496
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR124 contributes to glucocorticoid resistance in acute lymphoblastic leukemia by promoting proliferation, inhibiting apoptosis and targeting NR3C1.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-210 [13]

• Sensitive Disease: Paediatric acute lymphocytic leukemia [ICD-11: 2B33.4]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Dexamethasone
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MLL/AF4+ RS4 cells; Blood; Homo sapiens (Human); CVCL_0093
• In Vitro Model: TEL/AML1+ Reh cells; Blood; Homo sapiens (Human); CVCL_ZV66
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: Functioning as a hypoxamir (i.e. a microRNA whose expression is upregulated by hypoxia), miR-210 targets many genes involved in a wide range of physiological processes, such as cell survival/proliferation, mitochondrial metabolism, protein modification/transport, DNA damage repair and angiogenesis. Increasing/decreasing miR-210 expression using agomir/antagomir could enhance or reduce the response of Reh cells and RS4;11 cells to daunorubicin/dexamethasone/L-asparaginase and daunorubicin/dexamethasone/vincristine, respectively. miR-210 may be a good prognostic factor and a useful predictor of drug sensitivity, and is a potential therapeutic target for pediatric ALL.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-27a [18]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The expression of miR-331-5p and miR-27a was inversely correlated with MDR1 expression. Transfection of exogenous miR-27a or miR-331-5p, or a combination of these two miRNAs, down-regulated MDR1 and increased sensitivity of the k562-resistant cancer cells to DOX.

Key Molecule: hsa-miR-331-5p [18]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The expression of miR-331-5p and miR-27a was inversely correlated with MDR1 expression. Transfection of exogenous miR-27a or miR-331-5p, or a combination of these two miRNAs, down-regulated MDR1 and increased sensitivity of the k562-resistant cancer cells to DOX.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [19]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MCF-7/AdrVp cells; Breast; Homo sapiens (Human); CVCL_4Y46
• Experiment for Molecule Alteration: RT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The mRNA of the H19 gene is overexpressed in MCF-7/AdrVp cells relative toparental MCF-7 cells or drug-sensitive MCF-7/AdrVp revertant cells. H19is an imprinted gene with an important role in fetal differentiation, as well as a postulated function as a tumor suppressor gene. Another p95-over-expressing multidrug-resistant cell line, human lung carcinoma NCI-H1688, also displays high levels of 1119 mRNA.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [18]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The expression of miR-331-5p and miR-27a was inversely correlated with MDR1 expression. Transfection of exogenous miR-27a or miR-331-5p, or a combination of these two miRNAs, down-regulated MDR1 and increased sensitivity of the k562-resistant cancer cells to DOX.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Bcl-2 homologous antagonist/killer (BAK1) [20]

• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• 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.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 3 subfamily A member1 (CYP3A4) [21]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCRF-CEM cells; Pleural effusion; Homo sapiens (Human); CVCL_0207
• In Vitro Model: CEM/ADR5000 cells; Bone marrow; Homo sapiens (Human); CVCL_D544
• Experiment for Molecule Alteration: CYP450-Glo CYP 3A4 assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: In this study, resveratrol was a significant inhibitor of CYP3A4 enzyme activity with IC50 value 9.32 ( M). Moreover, the CYP3A4 mRNA levels were reduced after treatment with resveratrol 0.03-fold of the control levels with high significance (p < 0.001).

Key Molecule: Glutathione S-transferase (GST) [21]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCRF-CEM cells; Pleural effusion; Homo sapiens (Human); CVCL_0207
• In Vitro Model: CEM/ADR5000 cells; Bone marrow; Homo sapiens (Human); CVCL_D544
• Experiment for Molecule Alteration: Glutathione-S-transferase assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The Glutathione-S-transferases (GSTs) are a multigene family of dimeric proteins which play a central role in the detoxification of electrophilic xenobiotics and catalyze their conjugation with GSH to electrophilic metabolites, thus rendering them more water soluble. GSTs protect cells from cytotoxic and carcinogenic chemicals. GST activity was decreased by resveratrol in a dose dependent manner. IC50 value was 30.73 M. This results were confirmed by RT-PCR data, where the tested samples changed the GST mRNA level by 0.79-fold (p < 0.01) of control level.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-98 [22]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562/A02 cells; Blood; Homo sapiens (Human); CVCL_0368
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The targeted upregulated expression of miR98 could decrease the proliferation of leukemia cells and improve the sensitivity to chemotherapeutics by inhibiting E2F1 expression.

Key Molecule: hsa-miR-485-3p [23]

• Sensitive Disease: Lymphocytic leukemia [ICD-11: 2B33.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CEM cells; Pleural effusion; Homo sapiens (Human); N.A.
• In Vitro Model: CEM/VM-1-5 cells; Lymph; Homo sapiens (Human); CVCL_1B35
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-485-3p expression can mediate etoposide sensitivity indirectly by fine-tuning Top2alpha expression through the modification of NF-YB expression. Accordingly, miR-485-3p can be a putative therapeutic target to modulate etoposide resistance in tumor cells.

Key Molecule: hsa-mir-138 [3]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• 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: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [3]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• 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 blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin.

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [21]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CCRF-CEM cells; Pleural effusion; Homo sapiens (Human); CVCL_0207
• In Vitro Model: CEM/ADR5000 cells; Bone marrow; Homo sapiens (Human); CVCL_D544
• Experiment for Molecule Alteration: Efflux of rhodamine123 assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Resveratrol can restore the sensitivity of Caco-2 and CEM/ADR5000 cell lines to doxorubicin, through enhancing significantly doxorubicin cytotoxicity. ABC-transporter inhibitors, classified according to their action on ABC-transporters proteins into: 1. Function inhibitors, 2. Expression inhibitors, and 3. Functional and expression inhibitors, which have an ideal characters of ABC-transporters inhibitors. Our results indicate that resveratrol falls into the class 3 inhibitors.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Transcription factor E2F1 (E2F1) [22]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562/A02 cells; Blood; Homo sapiens (Human); CVCL_0368
• Experiment for Molecule Alteration: RT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The targeted upregulated expression of miR98 could decrease the proliferation of leukemia cells and improve the sensitivity to chemotherapeutics by inhibiting E2F1 expression.

Key Molecule: Nuclear transcription factor Y subunit beta (NFYB) [23]

• Sensitive Disease: Lymphocytic leukemia [ICD-11: 2B33.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CEM cells; Pleural effusion; Homo sapiens (Human); N.A.
• In Vitro Model: CEM/VM-1-5 cells; Lymph; Homo sapiens (Human); CVCL_1B35
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-485-3p expression can mediate etoposide sensitivity indirectly by fine-tuning Top2alpha expression through the modification of NF-YB expression. Accordingly, miR-485-3p can be a putative therapeutic target to modulate etoposide resistance in tumor cells.

Etoposide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-485-3p [23]

• Sensitive Disease: Lymphocytic leukemia [ICD-11: 2B33.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CEM cells; Pleural effusion; Homo sapiens (Human); N.A.
• In Vitro Model: CEM/VM-1-5 cells; Lymph; Homo sapiens (Human); CVCL_1B35
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-485-3p expression can mediate etoposide sensitivity indirectly by fine-tuning Top2alpha expression through the modification of NF-YB expression. Accordingly, miR-485-3p can be a putative therapeutic target to modulate etoposide resistance in tumor cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Nuclear transcription factor Y subunit beta (NFYB) [23]

• Sensitive Disease: Lymphocytic leukemia [ICD-11: 2B33.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CEM cells; Pleural effusion; Homo sapiens (Human); N.A.
• In Vitro Model: CEM/VM-1-5 cells; Lymph; Homo sapiens (Human); CVCL_1B35
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-485-3p expression can mediate etoposide sensitivity indirectly by fine-tuning Top2alpha expression through the modification of NF-YB expression. Accordingly, miR-485-3p can be a putative therapeutic target to modulate etoposide resistance in tumor cells.

Fluorouracil

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-138 [3]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [3]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• 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 blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin.

Hydroquinone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: FAS antisense RNA 1 (FAS-AS1) [24]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Down-regulation; Expression
• Resistant Drug: Hydroquinone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TK6 cells; Spleen; Homo sapiens (Human); CVCL_0561
• In Vivo Model: BALB/c nude mice model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Knockdown assay; Overexpression assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Aken together, these observations demonstrate crosstalk between FAS-AS1 and DNMT3b via a mutual inhibition loop and indicate a new mechanism by which FAS-AS1 regulates the expression of FAS in benzene-related carcinogenesis.

Imatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [25]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.T315I
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Mechanism Description: Different mutations within the kinase domain of BCR-ABL can be responsible for refractoriness of Ph+ leukaemia to STI571. Mutation in the BCR-ABL kinase domain might be a frequent mechanism of STI571 resistance in lymphoid disease. In summary, binding of STI571 to BCR-ABL depends on a number of specific interactions within the ATPbinding site. Our results strongly suggest that a patient could be resistant to STI571 by acquisition of different individual point mutations within the ATP-binding pocket or activation loop of BCR-ABL, even though the number of mutations might be limited. This factor could make it difficult to overcome resistance to STI571 by use of alternative kinase inhibitors.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [25]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.E255V
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Mechanism Description: Different mutations within the kinase domain of BCR-ABL can be responsible for refractoriness of Ph+ leukaemia to STI571. Mutation in the BCR-ABL kinase domain might be a frequent mechanism of STI571 resistance in lymphoid disease. In summary, binding of STI571 to BCR-ABL depends on a number of specific interactions within the ATPbinding site. Our results strongly suggest that a patient could be resistant to STI571 by acquisition of different individual point mutations within the ATP-binding pocket or activation loop of BCR-ABL, even though the number of mutations might be limited. This factor could make it difficult to overcome resistance to STI571 by use of alternative kinase inhibitors.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [26]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.G250E
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: PCR-Invader assay; Direct sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: The PCR-Invader assay used in this study is an appropriate tool for the screening of mutations during TkI therapy. High Sokal score is only predictive factor for emergence of mutation in CML-CP. P-loop mutations were associated with poor PFS in CML-CP.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [27]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.F359V
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: cDNA sequencing assay; Denaturing high-power liquid chromatography assay
• Mechanism Description: Our results confirm the high frequency of BCR-ABL kinase domain mutations in patients with secondary resistance to imatinib and exclude mutations of the activation loops of kIT, PDGFRA and PDGFRB as possible causes of resistance in patients without ABL mutations.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [27]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.D276G
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: cDNA sequencing assay; Denaturing high-power liquid chromatography assay
• Mechanism Description: Our results confirm the high frequency of BCR-ABL kinase domain mutations in patients with secondary resistance to imatinib and exclude mutations of the activation loops of kIT, PDGFRA and PDGFRB as possible causes of resistance in patients without ABL mutations.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [25], [27], [28]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.Y253H
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: Point mutations were found in the adenosine triphosphate (ATP) binding region of BCR/ABL in 12 of 18 patients with chronic myeloid leukemia (CML) or Ph-positive acute lymphoblastic leukemia (Ph+ ALL) and imatinib resistance (defined as loss of established hematologic response). Three mutations (T315I, Y253H, and F317L present in 3, 1, and 1 patients, respectively) have a predicted role in abrogating imatinib binding to BCR/ABL, whereas 3 other mutations (E255k, G250E, and M351T, present in 4, 2, and 2 patients, respectively) do not. Thus we confirm a high frequency of mutations clustered within the ATP-binding region of BCR/ABL in resistant patients.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [28]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.E255K
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: Point mutations were found in the adenosine triphosphate (ATP) binding region of BCR/ABL in 12 of 18 patients with chronic myeloid leukemia (CML) or Ph-positive acute lymphoblastic leukemia (Ph+ ALL) and imatinib resistance (defined as loss of established hematologic response). Three mutations (T315I, Y253H, and F317L present in 3, 1, and 1 patients, respectively) have a predicted role in abrogating imatinib binding to BCR/ABL, whereas 3 other mutations (E255k, G250E, and M351T, present in 4, 2, and 2 patients, respectively) do not. Thus we confirm a high frequency of mutations clustered within the ATP-binding region of BCR/ABL in resistant patients.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [29]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.M244V
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: CR-Abl sequencing assay
• Experiment for Drug Resistance: Event-free survival assay
• Mechanism Description: M244V and H396 mutations have been shown to be more resistant to imatinib but both have been shown to be sensitive to second generation TkI's such as nilotinib and dasatinib.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [25], [29]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.H396P
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: CR-Abl sequencing assay
• Experiment for Drug Resistance: Event-free survival assay
• Mechanism Description: M244V and H396 mutations have been shown to be more resistant to imatinib but both have been shown to be sensitive to second generation TkI's such as nilotinib and dasatinib.

Inotuzumab ozogamicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: B-cell receptor CD22 (CD22) [30]

• Resistant Disease: Relapsed B-acute Lymphoblastic leukaemia [ICD-11: 2B33.3]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Inotuzumab ozogamicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Experiment for Molecule Alteration: Flow cytometry assay
• Experiment for Drug Resistance: Enzyme-linked immunosorbent assay (ELISA)
• Mechanism Description: One important escape mechanism at relapse may be modulation of the CD22 antigen expression on leukemic blasts, analogous to antigen loss associated with CD19-directed therapies such as blinatumomab and CD19-CAR T-cell therapies.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: B-cell receptor CD22 (CD22) [31]

• Resistant Disease: Relapsed B-acute Lymphoblastic leukaemia [ICD-11: 2B33.3]
• Molecule Alteration: Missense mutation; p.V238 frameshift
• Resistant Drug: Inotuzumab ozogamicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Experiment for Molecule Alteration: Whole genome sequencing assay; Whole transcriptome RNA-sequencing assay
• Experiment for Drug Resistance: Bone marrow biopsy assay; Flow cytometry assay
• Mechanism Description: Decreased surface CD22 expression and receptor density have been reported as mechanisms of acquired@resistance to InO and CD22 CAR-T in some patients relapsing with B-lineage acute leukaemia. Truncating CD22 mutation with concomitant loss of the receptor from the cell surface represents a new mechanism of leukaemic cell escape

L-asparaginase

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-210 [13]

• Sensitive Disease: Paediatric acute lymphocytic leukemia [ICD-11: 2B33.4]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: L-asparaginase
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MLL/AF4+ RS4 cells; Blood; Homo sapiens (Human); CVCL_0093
• In Vitro Model: TEL/AML1+ Reh cells; Blood; Homo sapiens (Human); CVCL_ZV66
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: Functioning as a hypoxamir (i.e. a microRNA whose expression is upregulated by hypoxia), miR-210 targets many genes involved in a wide range of physiological processes, such as cell survival/proliferation, mitochondrial metabolism, protein modification/transport, DNA damage repair and angiogenesis. Increasing/decreasing miR-210 expression using agomir/antagomir could enhance or reduce the response of Reh cells and RS4;11 cells to daunorubicin/dexamethasone/L-asparaginase and daunorubicin/dexamethasone/vincristine, respectively. miR-210 may be a good prognostic factor and a useful predictor of drug sensitivity, and is a potential therapeutic target for pediatric ALL.

Larotrectinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: NT-3 growth factor receptor (TrkC) [32]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Other; .
• Sensitive Drug: Larotrectinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay

Mercaptopurine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [33]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Mercaptopurine
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Genome sequencing assay; Whole-exome sequencing assay
• Mechanism Description: Recent sequencing studies of T-ALL have confirmed the presence of these mutations as well as novel recurrent mutations in the tumor suppressor CNOT3, ribosomal proteins(RPL5 and RPL10) and in the setting of relapse, the NT5C2 gene, which inactivates nucleoside-analogue chemotherapy drugs.

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [34]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.R367Q
• Resistant Drug: Mercaptopurine
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Exome sequencing assay
• Experiment for Drug Resistance: Conality analyses assay
• Mechanism Description: These two NT5C2 mutations (R367Q, D407V) occur as recurrent mutational hotspots in relapse-ALL and they have been functionally validated. These mutations increase the NT5C2 inosine-5-monophosphate-nucleotidase activity; and therefore lead to resistance to one of the chemotherapeutic drugs, 6-mercaptopurine.

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [34]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.D407V
• Resistant Drug: Mercaptopurine
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Exome sequencing assay
• Experiment for Drug Resistance: Conality analyses assay
• Mechanism Description: These two NT5C2 mutations (R367Q, D407V) occur as recurrent mutational hotspots in relapse-ALL and they have been functionally validated. These mutations increase the NT5C2 inosine-5-monophosphate-nucleotidase activity; and therefore lead to resistance to one of the chemotherapeutic drugs, 6-mercaptopurine.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA mismatch repair protein Msh6 (MSH6) [35]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Structural variation; Copy number loss
• Resistant Drug: Mercaptopurine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• 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: Somatic copy number alteration assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Finally, relapse-specific focal deletion of MSH6 and, consequently, reduced gene expression were found in 2 of 20 cases. In an independent cohort of children with ALL, reduced expression of MSH6 was associated with resistance to mercaptopurine and prednisone, thereby providing a plausible mechanism by which this acquired deletion contributes to drug resistance at relapse.

Metformin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin-dependent kinase 1 (CDK1) [36]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Metformin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: LKB1/AMPk signaling pathway; Activation; hsa04152
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: ALL CEM cells; Lymph; Homo sapiens (Human); CVCL_0207
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: In metformin-sensitive cells, autophagy was not induced but rather it blocked proliferation by means of arresting cells in the S and G2/M phases which was associated with the downregulation of cyclin A, cyclin B1, and cdc2, but not that of cyclin E. In 10E1-CEM cells that overexpress Bcl-2 and are drug-resistant, the effect of metformin on proliferation was more pronounced, also inducing the activation of the caspases 3/7 and hence apoptosis.

Key Molecule: Cyclin-A2 (CCNA2) [36]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Metformin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: LKB1/AMPk signaling pathway; Activation; hsa04152
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: ALL CEM cells; Lymph; Homo sapiens (Human); CVCL_0207
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: In metformin-sensitive cells, autophagy was not induced but rather it blocked proliferation by means of arresting cells in the S and G2/M phases which was associated with the downregulation of cyclin A, cyclin B1, and cdc2, but not that of cyclin E. In 10E1-CEM cells that overexpress Bcl-2 and are drug-resistant, the effect of metformin on proliferation was more pronounced, also inducing the activation of the caspases 3/7 and hence apoptosis.

Key Molecule: G2/mitotic-specific cyclin-B1 (CCNB1) [36]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Metformin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: LKB1/AMPk signaling pathway; Activation; hsa04152
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: ALL CEM cells; Lymph; Homo sapiens (Human); CVCL_0207
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: In metformin-sensitive cells, autophagy was not induced but rather it blocked proliferation by means of arresting cells in the S and G2/M phases which was associated with the downregulation of cyclin A, cyclin B1, and cdc2, but not that of cyclin E. In 10E1-CEM cells that overexpress Bcl-2 and are drug-resistant, the effect of metformin on proliferation was more pronounced, also inducing the activation of the caspases 3/7 and hence apoptosis.

Methotrexate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase KRas (KRAS) [15]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.Q61H
• Resistant Drug: Methotrexate
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Mouse model; Mus musculus
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Whole-genome sequencing assay
• Experiment for Drug Resistance: Flow cytometric analysis assay; MTT assay
• Mechanism Description: Notably, drug response a.lyses in isogenic kras wild-type and kras G12D cells showed increased resistance to methotrexate (P < 0.001) upon oncogenic kras activation.

Key Molecule: GTPase KRas (KRAS) [15]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.G12D
• Resistant Drug: Methotrexate
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Mouse model; Mus musculus
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Whole-genome sequencing assay
• Experiment for Drug Resistance: Flow cytometric analysis assay; MTT assay
• Mechanism Description: Notably, drug response a.lyses in isogenic kras wild-type and kras G12D cells showed increased resistance to methotrexate (P < 0.001) upon oncogenic kras activation.

Key Molecule: Hematopoietic SH2 domain containing (HSH2D) [37]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Methotrexate
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HuT-78 cells; Peripheral blood; Homo sapiens (Human); CVCL_0337
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The expression of HSH2D was downregulated in T-ALL compared with B-cell ALL. Western blotting and reverse transcription-quantitative PCR demonstrated that the overexpression of HSH2 resulted in the inhibition of CD28-mediated IL-2 activation. In related experiments with drug-resistant cell lines, it was determined that HSH2D expression is necessary for HuT-78 cells to be resistant to MTX.

Ponatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [38]

• Resistant Disease: Relapsed acute lymphocytic leukemia [ICD-11: 2B33.5]
• Molecule Alteration: Missense mutation; p.T315I
• Resistant Drug: Ponatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay
• Mechanism Description: Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [38]

• Resistant Disease: Relapsed acute lymphocytic leukemia [ICD-11: 2B33.5]
• Molecule Alteration: Missense mutation; p.D276G
• Resistant Drug: Ponatinib
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay
• Mechanism Description: Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations.

Prednisolone

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-335 [39]

• Sensitive Disease: Paediatric acute lymphocytic leukemia [ICD-11: 2B33.4]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Prednisolone
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: MAPK signaling pathway; Regulation; hsa04010
• Cell Pathway Regulation: NF-kappaB signaling pathway; Regulation; hsa04064
• In Vitro Model: MLL/AF4+ RS4 cells; Blood; Homo sapiens (Human); CVCL_0093
• In Vitro Model: 697 cells; Bone marrow; Homo sapiens (Human); CVCL_0079
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: MAPk1 is a novel target of MIR335, and that MEk/ERk inhibitor treatment enhanced prednisolone-induced cell death through the activation of BIM (BCL2L11).

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [39]

• Sensitive Disease: Paediatric acute lymphocytic leukemia [ICD-11: 2B33.4]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Prednisolone
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: MAPK signaling pathway; Regulation; hsa04010
• Cell Pathway Regulation: NF-kappaB signaling pathway; Regulation; hsa04064
• In Vitro Model: MLL/AF4+ RS4 cells; Blood; Homo sapiens (Human); CVCL_0093
• In Vitro Model: 697 cells; Bone marrow; Homo sapiens (Human); CVCL_0079
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: MAPk1 is a novel target of MIR335, and that MEk/ERk inhibitor treatment enhanced prednisolone-induced cell death through the activation of BIM (BCL2L11).

Prednisone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA mismatch repair protein Msh6 (MSH6) [35]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Structural variation; Copy number loss
• Resistant Drug: Prednisone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Peripheral blood; Blood; Homo sapiens (Human); N.A.
• 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: Somatic copy number alteration assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Finally, relapse-specific focal deletion of MSH6 and, consequently, reduced gene expression were found in 2 of 20 cases. In an independent cohort of children with ALL, reduced expression of MSH6 was associated with resistance to mercaptopurine and prednisone, thereby providing a plausible mechanism by which this acquired deletion contributes to drug resistance at relapse.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: HOXA cluster antisense RNA 2 (HOXA-AS2) [16]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Prednisone
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR/RAS/RAF/MEK/ERK signaling pathway; Activation; hsa01521
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: CCRF-CEM cells; Pleural effusion; Homo sapiens (Human); CVCL_0207
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: TCF7L2 activated HOXA-AS2 decreased the glucocorticoid sensitivity in acute lymphoblastic leukemia through regulating HOXA3/EGFR/Ras/Raf/MEk/ERk pathway.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Homeobox protein Hox-A3 (HOXA3) [16]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Prednisone
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR/RAS/RAF/MEK/ERK signaling pathway; Activation; hsa01521
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: CCRF-CEM cells; Pleural effusion; Homo sapiens (Human); CVCL_0207
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: TCF7L2 activated HOXA-AS2 decreased the glucocorticoid sensitivity in acute lymphoblastic leukemia through regulating HOXA3/EGFR/Ras/Raf/MEk/ERk pathway.

Ruxolitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [40]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.R938Q (c.2813G>A)
• Resistant Drug: Ruxolitinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Drug Resistance: FACS assay
• Mechanism Description: Mutations within the kinase domain of JAK2 are associated with resistance to type I JAK inhibitors.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Janus kinase 1 (JAK-1) [41]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.S646F (c.1937C>T)
• Sensitive Drug: Ruxolitinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Phosphoflow analysis
• Mechanism Description: The missense mutation p.S646F (c.1937C>T) in gene JAK1 cause the sensitivity of Ruxolitinib by aberration of the drug's therapeutic target

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [41]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.R683G (c.2047A>G)
• Sensitive Drug: Ruxolitinib
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Interleukin-7 receptor subunit alpha (IL7R) [41]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.S185C (c.553A>T)
• Sensitive Drug: Ruxolitinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [42]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.F694L (c.2080T>C)
• Sensitive Drug: Ruxolitinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT3 signaling pathway; Inhibition; hsa04030

Thioguanine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [33]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Thioguanine
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Genome sequencing assay; Whole-exome sequencing assay
• Mechanism Description: Recent sequencing studies of T-ALL have confirmed the presence of these mutations as well as novel recurrent mutations in the tumor suppressor CNOT3, ribosomal proteins(RPL5 and RPL10) and in the setting of relapse, the NT5C2 gene, which inactivates nucleoside-analogue chemotherapy drugs.

Vincristine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-100 [43]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: ETV6-RUNX1-positive Reh cells; Blood; Homo sapiens (Human); CVCL_1650
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-125b (miR-125b), miR-99a and miR-100 are overexpressed in vincristine-resistant acute lymphoblastic leukemia (ALL).

Key Molecule: hsa-mir-125b [43]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: ETV6-RUNX1-positive Reh cells; Blood; Homo sapiens (Human); CVCL_1650
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-125b (miR-125b), miR-99a and miR-100 are overexpressed in vincristine-resistant acute lymphoblastic leukemia (ALL).

Key Molecule: hsa-mir-99a [43]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: ETV6-RUNX1-positive Reh cells; Blood; Homo sapiens (Human); CVCL_1650
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-125b (miR-125b), miR-99a and miR-100 are overexpressed in vincristine-resistant acute lymphoblastic leukemia (ALL).

Key Molecule: H19, imprinted maternally expressed transcript (H19) [19]

• Resistant Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MCF-7/AdrVp cells; Breast; Homo sapiens (Human); CVCL_4Y46
• Experiment for Molecule Alteration: RT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The mRNA of the H19 gene is overexpressed in MCF-7/AdrVp cells relative toparental MCF-7 cells or drug-sensitive MCF-7/AdrVp revertant cells. H19is an imprinted gene with an important role in fetal differentiation, as well as a postulated function as a tumor suppressor gene. Another p95-over-expressing multidrug-resistant cell line, human lung carcinoma NCI-H1688, also displays high levels of 1119 mRNA.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-210 [13]

• Sensitive Disease: Paediatric acute lymphocytic leukemia [ICD-11: 2B33.4]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Vincristine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MLL/AF4+ RS4 cells; Blood; Homo sapiens (Human); CVCL_0093
• In Vitro Model: TEL/AML1+ Reh cells; Blood; Homo sapiens (Human); CVCL_ZV66
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: Functioning as a hypoxamir (i.e. a microRNA whose expression is upregulated by hypoxia), miR-210 targets many genes involved in a wide range of physiological processes, such as cell survival/proliferation, mitochondrial metabolism, protein modification/transport, DNA damage repair and angiogenesis. Increasing/decreasing miR-210 expression using agomir/antagomir could enhance or reduce the response of Reh cells and RS4;11 cells to daunorubicin/dexamethasone/L-asparaginase and daunorubicin/dexamethasone/vincristine, respectively. miR-210 may be a good prognostic factor and a useful predictor of drug sensitivity, and is a potential therapeutic target for pediatric ALL.

Key Molecule: hsa-mir-138 [3]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Vincristine
• 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: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [3]

• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vincristine
• 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 blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin.

Clinical Trial Drug(s) 3 drug(s) in total

Camptothecin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-181a [44]

• Sensitive Disease: Paediatric acute lymphocytic leukemia [ICD-11: 2B33.4]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Camptothecin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: CCRF-CEM cells; Pleural effusion; Homo sapiens (Human); CVCL_0207
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Abnormal high expression of miR-181a in bone marrow and Cim-C1 cells in ALL children, inhibition of Mir-181A expression in Cim-C1 cells can significantly increase drug sensitivity of CIM-C1 cells, and upregulation of Mir-181A expression in CCRF-CEM cells can significantly increase drug resistance of CCRF-CEM cells.

E6201

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [45]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.D835G (c.2504A>G)
• Sensitive Drug: E6201
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: NOG mouse; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion method assay; FACS assay
• Mechanism Description: E6201 exerts marked anti-leukemia effects in AML cells and activation of MEK/ERK signaling pathway by NRAS mutation sensitizes E6201-induced pro-apoptotic effects in AML cells.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [45]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Sensitive Drug: E6201
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: NOG mouse; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion method assay; FACS assay
• Mechanism Description: E6201 exerts marked anti-leukemia effects in AML cells and activation of MEK/ERK signaling pathway by NRAS mutation sensitizes E6201-induced pro-apoptotic effects in AML cells.

LY-3023414

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PI3-kinase alpha (PIK3CA) [46]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Sensitive Drug: LY-3023414
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: NCI-H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• In Vitro Model: AsPC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0152
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: MSTO-211H cells; Lung; Homo sapiens (Human); CVCL_1430
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: NCI-H1734 cells; Lung; Homo sapiens (Human); CVCL_1491
• In Vitro Model: NCI-H1395 cells; Lung; Homo sapiens (Human); CVCL_1467
• In Vitro Model: NCI-H226 cells; Pleural effusion; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCI-H1993 cells; Lymph node; Homo sapiens (Human); CVCL_1512
• In Vitro Model: NCI-H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: NCI-H1299 cells; Lymph node; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI- H460 cells; Pleural effusion; Homo sapiens (Human); CVCL_0459
• In Vitro Model: ACC-MESO-4 cells; Pleural epithelium; Homo sapiens (Human); CVCL_5114
• In Vitro Model: ACC-MESO-1 cells; Pleural epithelium; Homo sapiens (Human); CVCL_5113
• Experiment for Drug Resistance: CellTitre-Glo assay; Caspase-Glo 3/7 assay

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

MEK inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase KRas (KRAS) [47]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.G12 (c.34_36)
• Sensitive Drug: MEK inhibitors
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CellTiter 96 Aqueous One assay
• Mechanism Description: The missense mutation p.G12 (c.34_36) in gene KRAS cause the sensitivity of MEK inhibitors by unusual activation of pro-survival pathway

PD98059

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [48]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.E76K (c.226G>A)
• Sensitive Drug: PD98059
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The missense mutation p.E76K (c.226G>A) in gene PTPN11 cause the sensitivity of PD98059 by unusual activation of pro-survival pathway

Thiopurine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [15]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.R238W
• Resistant Drug: Thiopurine
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Whole-genome sequencing assay
• Experiment for Drug Resistance: Flow cytometric analysis assay; MTT assay
• Mechanism Description: Finally, genomic profiling of diagnostic and relapsed leukemias has identified relapse-associated mutations in the 5'-nucleotidase, cytosolic II(NT5C2) gene as drivers of resistance to thiopurine chemotherapy in about 20% of T-ALL and 5% of B-precursor ALL cases at relapse.

U0126

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [48]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Molecule Alteration: Missense mutation; p.E76K (c.226G>A)
• Sensitive Drug: U0126
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The missense mutation p.E76K (c.226G>A) in gene PTPN11 cause the sensitivity of U0126 by unusual activation of pro-survival pathway

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