Molecule Information

General Information of the Molecule (ID: Mol00819)

• Name: BCR-ABL1 e8a2 variant (BCR-ABL1) ,Homo sapiens
• Synonyms: BCR-ABL1; Fragment
• Molecule Type: Protein
• Gene Name: BCR-ABL1
• Sequence:
  QNSQQSFDSSSPPTPQCHKRHRHCPVVVSEATIVGVRKTGQIWPNDGEGAFHGDADGSFG
  TPPGYGCAADRAEEQRRHQDGLPYIDDSPSSSPHLSSKGRGSRDALVSGALESTKASELD
  LEKGLEMRKWVLSGILASEETYLSHLEALLLPMKPLKAAATTSQPVLTSQQIETIFFKVP
  ELYEIHKEFYDGLFPRVQQWSHQQRVGDLFQKLASQLGVYRAFVDNYGVAMEMAEKCCQA
  NAQFAEISENLRARSNKDAKDPTTKNSLETLLYKPVDRVTRSTLVLHDLLKHTPASHPDH
  PLLQDALRISQNFLSSINEEITPRRQSMTVKKGELLNRKDKTTFEKLDYLMSKEDNYKRT
  REYIRSLKMVPSIPYLEALQRPVASDFEPQGLSEAARWNSKENLLAGPSENDPNLFVALY
  DFVASGDNTLSITKGEKLRVLGYNHNGE
• Uniprot ID: E7E8T7_HUMAN

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Dasatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Chronic myeloid leukemia [1], [2], [3]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Dasatinib
• Molecule Alteration: Missense mutation; p.F317L
• 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
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: After 13 months of therapy a progression of disease to accelerated phase was detected and a second mutational screening analysis performed at that time revealed the absence of M244 V and the appearance of M351T mutation. After 14 months of therapy, a third mutational analysis was performed which revealed the disappearance of M351T mutation and the acquisition of a new F317L mutation.

Disease Class: Chronic myeloid leukemia [4]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Dasatinib
• Molecule Alteration: Missense mutation; p.D276G
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: RNA sequencing assay
• Mechanism Description: The presence of BCR-ABL oncogene mutations in patients with chronic myeloid leukemia (CML) may be responsible for the failure of tyrosine kinase inhibitor (TkI) treatment. In addition to 9 point mutations (G250E / F317L, F359V, L387M, Y253H, M388L, M244V, T315I, D276G), 35 bp insertion between exons 8 and 9 and deletion exon 7 were detected. Our results demonstrate that direct sequencing is suitable for routine clinical monitoring patients with CML and may be useful for optimizing therapy.

Disease Class: Chronic myeloid leukemia [5]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Dasatinib
• Molecule Alteration: Missense mutation; p.V299L
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: In patients treated sequentially with dasatinib, nilotinib, or both TkIs after imatinib failure who had developed resistance to second-line treatment, analysis of the individual components of the compound mutations revealed that the identities of component mutations reflected the type of prior drug exposure. Therefore, in all patients treated with dasatinib, at least 1 component of the compound mutations was V299L, F317L, or E255k, all of which have been reported in clinical or in vitro resistance to dasatinib.

Disease Class: Chronic myeloid leukemia [5]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Dasatinib
• Molecule Alteration: Missense mutation; p.F317L
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: In patients treated sequentially with dasatinib, nilotinib, or both TkIs after imatinib failure who had developed resistance to second-line treatment, analysis of the individual components of the compound mutations revealed that the identities of component mutations reflected the type of prior drug exposure. Therefore, in all patients treated with dasatinib, at least 1 component of the compound mutations was V299L, F317L, or E255k, all of which have been reported in clinical or in vitro resistance to dasatinib.

Disease Class: Chronic myeloid leukemia [5]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Dasatinib
• Molecule Alteration: Missense mutation; p.E255K
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: In patients treated sequentially with dasatinib, nilotinib, or both TkIs after imatinib failure who had developed resistance to second-line treatment, analysis of the individual components of the compound mutations revealed that the identities of component mutations reflected the type of prior drug exposure. Therefore, in all patients treated with dasatinib, at least 1 component of the compound mutations was V299L, F317L, or E255k, all of which have been reported in clinical or in vitro resistance to dasatinib.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [6]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Dasatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: CCk reagent assay; Flow cytometry assay
• Mechanism Description: CircBA9.3 promoted cell proliferation and reduced the sensitivity of leukaemic cells to TkIs through up-regulation of the ABL1 and BCR-ABL1 protein expression levels.

Imatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Chronic myeloid leukemia [7], [8], [9]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.F359V
• 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: Direct sequencing assay
• Mechanism Description: Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255k, M351T, H396R, S417Y, E450k and E459k disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459k, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).

Disease Class: Chronic myeloid leukemia [10]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.Q252M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Pyrosequencing analysis
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: Imatinib resistance in chronic myeloid leukemia (CML) is commonly due to BCR-ABL kinase domain mutations (kDMs).

Disease Class: Chronic myeloid leukemia [10]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.P310S
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Pyrosequencing analysis
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: Imatinib resistance in chronic myeloid leukemia (CML) is commonly due to BCR-ABL kinase domain mutations (kDMs).

Disease Class: Chronic myeloid leukemia [11]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Structural mutation; Structural variation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: ASO-PCR and sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutations in the kinase domain (kD) of BCR-ABL are the leading cause of acquired imatinib resistance.

Disease Class: Acute lymphocytic leukemia [12], [13], [14]

• Resistant Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.Y253H
• 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.

Disease Class: Chronic myeloid leukemia [15]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.L387F
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Bidirectional DNA sequencing method assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: This report expands the spectrum of BCR-ABL mutations and stresses the use of mutation testing in imatinib-resistant patients for continuation of treatment procedure. The most commonly mutated region was drug-binding site (29%) followed by P-loop region (26%) and most patients bearing them were in accelerated phase and blastic phase.

Disease Class: Chronic myeloid leukemia [15], [16], [17]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.E459G
• 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: Bidirectional DNA sequencing method assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: This report expands the spectrum of BCR-ABL mutations and stresses the use of mutation testing in imatinib-resistant patients for continuation of treatment procedure. The most commonly mutated region was drug-binding site (29%) followed by P-loop region (26%) and most patients bearing them were in accelerated phase and blastic phase.

Disease Class: Chronic myeloid leukemia [15]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.E453A
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Bidirectional DNA sequencing method assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: This report expands the spectrum of BCR-ABL mutations and stresses the use of mutation testing in imatinib-resistant patients for continuation of treatment procedure. The most commonly mutated region was drug-binding site (29%) followed by P-loop region (26%) and most patients bearing them were in accelerated phase and blastic phase.

Disease Class: Chronic myeloid leukemia [15]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.E279A
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Bidirectional DNA sequencing method assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: This report expands the spectrum of BCR-ABL mutations and stresses the use of mutation testing in imatinib-resistant patients for continuation of treatment procedure. The most commonly mutated region was drug-binding site (29%) followed by P-loop region (26%) and most patients bearing them were in accelerated phase and blastic phase.

Disease Class: Chronic myeloid leukemia [15]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.D276N
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Bidirectional DNA sequencing method assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: This report expands the spectrum of BCR-ABL mutations and stresses the use of mutation testing in imatinib-resistant patients for continuation of treatment procedure. The most commonly mutated region was drug-binding site (29%) followed by P-loop region (26%) and most patients bearing them were in accelerated phase and blastic phase.

Disease Class: Chronic myeloid leukemia [15]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.S438C
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Bidirectional DNA sequencing method assay
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: This report expands the spectrum of BCR-ABL mutations and stresses the use of mutation testing in imatinib-resistant patients for continuation of treatment procedure. The most commonly mutated region was drug-binding site (29%) followed by P-loop region (26%) and most patients bearing them were in accelerated phase and blastic phase.

Disease Class: Chronic myeloid leukemia [17]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.E453D
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Disease Class: Chronic myeloid leukemia [17]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.E352G
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Disease Class: Chronic myeloid leukemia [17]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.E352D
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Disease Class: Chronic myeloid leukemia [17]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.E282G
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Disease Class: Chronic myeloid leukemia [17]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.E279Z
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Disease Class: Chronic myeloid leukemia [17]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.D482V
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Disease Class: Chronic myeloid leukemia [7]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.Q252R
• 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: We identified BCR-ABL kinase domain mutations in 29 of 32 patients whose disease relapsed after an initial response to the tyrosine kinase inhibitor imatinib. Fifteen different amino acid substitutions affecting 13 residues in the kinase domain were found. Mutations fell into two groups-those that alter amino acids that directly contact imatinib and those postulated to prevent BCR-ABL from achieving the inactive conformational state required for imatinib binding. Distinct mutations conferred varying degrees of imatinib resistance. Mutations detected in a subset of patients with stable chronic phase disease correlated with subsequent disease progression.

Disease Class: Chronic myeloid leukemia [7]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.M343T
• 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: We identified BCR-ABL kinase domain mutations in 29 of 32 patients whose disease relapsed after an initial response to the tyrosine kinase inhibitor imatinib. Fifteen different amino acid substitutions affecting 13 residues in the kinase domain were found. Mutations fell into two groups-those that alter amino acids that directly contact imatinib and those postulated to prevent BCR-ABL from achieving the inactive conformational state required for imatinib binding. Distinct mutations conferred varying degrees of imatinib resistance. Mutations detected in a subset of patients with stable chronic phase disease correlated with subsequent disease progression.

Disease Class: Chronic myeloid leukemia [5]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.V299L
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: In patients treated sequentially with dasatinib, nilotinib, or both TkIs after imatinib failure who had developed resistance to second-line treatment, analysis of the individual components of the compound mutations revealed that the identities of component mutations reflected the type of prior drug exposure. Therefore, in all patients treated with dasatinib, at least 1 component of the compound mutations was V299L, F317L, or E255k, all of which have been reported in clinical or in vitro resistance to dasatinib.

Disease Class: Chronic myeloid leukemia [5]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.F317L
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: In patients treated sequentially with dasatinib, nilotinib, or both TkIs after imatinib failure who had developed resistance to second-line treatment, analysis of the individual components of the compound mutations revealed that the identities of component mutations reflected the type of prior drug exposure. Therefore, in all patients treated with dasatinib, at least 1 component of the compound mutations was V299L, F317L, or E255k, all of which have been reported in clinical or in vitro resistance to dasatinib.

Disease Class: Chronic myeloid leukemia [5]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.E255K
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: In patients treated sequentially with dasatinib, nilotinib, or both TkIs after imatinib failure who had developed resistance to second-line treatment, analysis of the individual components of the compound mutations revealed that the identities of component mutations reflected the type of prior drug exposure. Therefore, in all patients treated with dasatinib, at least 1 component of the compound mutations was V299L, F317L, or E255k, all of which have been reported in clinical or in vitro resistance to dasatinib.

Disease Class: Chronic myeloid leukemia [7], [8], [9]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.L387M
• 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: cDNA sequencing assay; Standard dideoxy chain-termination DNA sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TkIs and can help in therapy selection.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [6]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Expression; Up-regulation
• 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: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: CCk reagent assay; Flow cytometry assay
• Mechanism Description: CircBA9.3 promoted cell proliferation and reduced the sensitivity of leukaemic cells to TkIs through up-regulation of the ABL1 and BCR-ABL1 protein expression levels.

Disease Class: Chronic myeloid leukemia [17]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Missense mutation; p.R328M
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable. kinase domain mutations predict a shorter progression-free survival.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [18]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Sensitive Drug: Imatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: JAKT/STAT/PI3K/AKT signaling pathway; Inhibition; hsa04630
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• 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: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Meg-01 cells; Blood; Homo sapiens (Human); CVCL_0425
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: Luciferase assay verified that miR-30e directly targets ABL. Enforced expression of miR-30e in k562 cells suppressed proliferation and induced apoptosis of these cells and sensitized them to imatinib treatment. These findings strongly suggest that miR-30e acts as a tumor suppressor by downregulating BCR-ABL expression.

Nilotinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Chronic myeloid leukemia [4]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Nilotinib
• Molecule Alteration: Missense mutation; p.F359V
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: RNA sequencing assay
• Mechanism Description: The presence of BCR-ABL oncogene mutations in patients with chronic myeloid leukemia (CML) may be responsible for the failure of tyrosine kinase inhibitor (TkI) treatment. In addition to 9 point mutations (G250E / F317L, F359V, L387M, Y253H, M388L, M244V, T315I, D276G), 35 bp insertion between exons 8 and 9 and deletion exon 7 were detected. Our results demonstrate that direct sequencing is suitable for routine clinical monitoring patients with CML and may be useful for optimizing therapy.

Disease Class: Chronic myeloid leukemia [4]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Nilotinib
• Molecule Alteration: Missense mutation; p.F317L
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: RNA sequencing assay
• Mechanism Description: The presence of BCR-ABL oncogene mutations in patients with chronic myeloid leukemia (CML) may be responsible for the failure of tyrosine kinase inhibitor (TkI) treatment. In addition to 9 point mutations (G250E / F317L, F359V, L387M, Y253H, M388L, M244V, T315I, D276G), 35 bp insertion between exons 8 and 9 and deletion exon 7 were detected. Our results demonstrate that direct sequencing is suitable for routine clinical monitoring patients with CML and may be useful for optimizing therapy.

Disease Class: Chronic myeloid leukemia [4]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Nilotinib
• Molecule Alteration: Missense mutation; p.D276G
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: RNA sequencing assay
• Mechanism Description: The presence of BCR-ABL oncogene mutations in patients with chronic myeloid leukemia (CML) may be responsible for the failure of tyrosine kinase inhibitor (TkI) treatment. In addition to 9 point mutations (G250E / F317L, F359V, L387M, Y253H, M388L, M244V, T315I, D276G), 35 bp insertion between exons 8 and 9 and deletion exon 7 were detected. Our results demonstrate that direct sequencing is suitable for routine clinical monitoring patients with CML and may be useful for optimizing therapy.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [6]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Nilotinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: Ku812 cells; Bone marrow; Homo sapiens (Human); CVCL_0379
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: CCk reagent assay; Flow cytometry assay
• Mechanism Description: CircBA9.3 promoted cell proliferation and reduced the sensitivity of leukaemic cells to TkIs through up-regulation of the ABL1 and BCR-ABL1 protein expression levels.

Ponatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Chronic myeloid leukemia [19]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Ponatinib
• Molecule Alteration: Missense mutation; p.H396R
• 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.

Disease Class: Chronic myeloid leukemia [19]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Ponatinib
• Molecule Alteration: Missense mutation; p.G250E
• 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.

Disease Class: Chronic myeloid leukemia [19]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Ponatinib
• Molecule Alteration: Missense mutation; p.F359V
• 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.

Disease Class: Chronic myeloid leukemia [19]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Ponatinib
• Molecule Alteration: Missense mutation; p.F359I
• 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.

Disease Class: Chronic myeloid leukemia [19]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Ponatinib
• Molecule Alteration: Missense mutation; p.F359C
• 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.

Disease Class: Chronic myeloid leukemia [19]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Ponatinib
• Molecule Alteration: Missense mutation; p.F317L
• 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.

Disease Class: Chronic myeloid leukemia [19]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Ponatinib
• Molecule Alteration: Missense mutation; p.E453K
• 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.

Disease Class: Chronic myeloid leukemia [19]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Ponatinib
• Molecule Alteration: Missense mutation; p.E279K
• 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.

Disease Class: Relapsed acute lymphocytic leukemia [19]

• Resistant Disease: Relapsed acute lymphocytic leukemia [ICD-11: 2B33.5]
• Resistant Drug: Ponatinib
• Molecule Alteration: Missense mutation; p.T315I
• 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.

Disease Class: Relapsed acute lymphocytic leukemia [19]

• Resistant Disease: Relapsed acute lymphocytic leukemia [ICD-11: 2B33.5]
• Resistant Drug: Ponatinib
• Molecule Alteration: Missense mutation; p.D276G
• 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.

Sorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hepatocellular carcinoma [20]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and its nuclear expression is promoted by miR-21, whose nuclear translocation is induced by sorafenib.

Investigative Drug(s) 1 drug(s) in total

Tyrosine kinase inhibitor

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Chronic myeloid leukemia [10]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Tyrosine kinase inhibitor
• Molecule Alteration: Missense mutation; p.L324Q
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Pyrosequencing analysis
• Experiment for Drug Resistance: Progression-free survival assay; Overall survival assay
• Mechanism Description: Imatinib resistance in chronic myeloid leukemia (CML) is commonly due to BCR-ABL kinase domain mutations (kDMs).

References

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