Drug Information

Drug (ID: DG00007) and It's Reported Resistant Information

• Name: Nilotinib
• Synonyms: NIL; Nilotinibum; Tasigna (Novartis); Nilotinib (INN/USAN); Nilotinib, AMN107, Tasigna; Tasigna, AMN-107, Nilotinib; L-1-yl)-3-(trifluoromethyl)phenyl]benzamide; Benzamide, 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-(9CI); 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazo; 4-Methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; 4-Methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]benzamide; 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide; Nilotinib (BCR-ABL inhibitor 2nd gen)
• Indication:
  In total 1 Indication(s)
  Myeloproliferative neoplasm [ICD-11: 2A22]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Breast cancer [ICD-11: 2C60]; [2]
  Chronic myeloid leukemia [ICD-11: 2A20]; [3]
  Gastrointestinal cancer [ICD-11: 2B5B]; [4]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Chronic myeloid leukemia [ICD-11: 2A20]; [1]
• Target: Fusion protein Bcr-Abl (Bcr-Abl); BCR_HUMAN-ABL1_HUMAN; [1]
• Formula: C28H22F3N7O
• IsoSMILES: CC1=C(C=C(C=C1)C(=O)NC2=CC(=CC(=C2)C(F)(F)F)N3C=C(N=C3)C)NC4=NC=CC(=N4)C5=CN=CC=C5
• InChI: 1S/C28H22F3N7O/c1-17-5-6-19(10-25(17)37-27-33-9-7-24(36-27)20-4-3-8-32-14-20)26(39)35-22-11-21(28(29,30)31)12-23(13-22)38-15-18(2)34-16-38/h3-16H,1-2H3,(H,35,39)(H,33,36,37)
• InChIKey: HHZIURLSWUIHRB-UHFFFAOYSA-N
• PubChem CID: 644241
• ChEBI ID: CHEBI:52172
• TTD Drug ID: D00STL
• VARIDT ID: DR00013
• DrugBank ID: DB04868

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Chronic myeloid leukemia [ICD-11: 2A20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [3]

• Molecule Alteration: Missense mutation; p.M351T
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• 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.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [5]

• Molecule Alteration: Missense mutation; p.F359C
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next generation sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: HSCT is an important salvage option for TkI-resistant patients with or without BCR-ABL1 mutations. Patients with mutations were more likely to develop advanced disease and had worse outcomes after HSCT.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [5]

• Molecule Alteration: Missense mutation; p.E255V
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next generation sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: HSCT is an important salvage option for TkI-resistant patients with or without BCR-ABL1 mutations. Patients with mutations were more likely to develop advanced disease and had worse outcomes after HSCT.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [5]

• Molecule Alteration: Missense mutation; p.E255K
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next generation sequencing assay
• Experiment for Drug Resistance: Event-free survival assay; Overall survival assay
• Mechanism Description: HSCT is an important salvage option for TkI-resistant patients with or without BCR-ABL1 mutations. Patients with mutations were more likely to develop advanced disease and had worse outcomes after HSCT.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6], [7]

• Molecule Alteration: Missense mutation; p.T315I
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• 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: Our finding reflects the natural development of a T315I mutation within the hematopoietic system of the reported patient and indicates the importance of BCR-ABL1 mutation monitoring in more primitive cell populations. Considering the natural history of T315I development in this reported CML case, we hypothesize that BCR-ABL1 kD mutations may be pre-concentrated in more primitive CML cells, which subsequently expand into the PB.

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

• Molecule Alteration: Missense mutation; p.F359I
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Mechanism Description: The most common mechanism of acquired resistance in CML in imatinib era is the acquisition of BCR-ABL kinase domain mutations with decreased sensitivity to the drug. Our findings demonstrate the potential hazards of sequential kinase inhibitor therapy and suggest a role for a combination of ABL kinase inhibitors, perhaps including drugs with different mechanisms of action, to prevent the outgrowth of cells harboring drug-resistant BCR-ABL mutations.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6]

• Molecule Alteration: Missense mutation; p.L387M
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• 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.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6], [8], [9]

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

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [6]

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

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [6]

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

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [6]

• Molecule Alteration: Missense mutation; p.D276G
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• 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.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [6], [10]

• Molecule Alteration: Missense mutation; p.Y253H
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• 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 confirm the previously described poor prognosis of CML patients with mutations in the BCR-ABL1 kD, since 40.0% of our CML patients who harbored a BCR-ABL1 kD mutation died from CML while receiving TkI treatment.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [10]

• Molecule Alteration: Missense mutation; p.H396R
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• 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 confirm the previously described poor prognosis of CML patients with mutations in the BCR-ABL1 kD, since 40.0% of our CML patients who harbored a BCR-ABL1 kD mutation died from CML while receiving TkI treatment.

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [11]

• Molecule Alteration: Missense mutation; p.T315V
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: Tritiated thymidine incorporation assay
• Mechanism Description: Mutations may impair TkI activity by directly or indirectly impairing the drug binding to the protein. We report the discovery of three new BCR/ABL mutations, L248R, T315V, and F317R identified in two patients with CML (L248R and T315V) and in one patient with Ph+ acute lymphoblastic leukemia (ALL) (F317R).

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa_circ_BA9.3 [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• 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: 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.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• 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.

Key Molecule: BCR-ABL1 e8a2 variant (BCR-ABL1) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• 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.

Key Molecule: GTPase Nras (NRAS) [12], [13]

• Molecule Alteration: Missense mutation; p.G12V
• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT signaling pathway; Activation; hsa04030
• Cell Pathway Regulation: RAF/KRAS/MEK signaling pathway; Activation; hsa04010
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: KCL-22 cells; Bone marrow; Homo sapiens (Human); CVCL_2091
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay; Sanger Sequencing assay
• Mechanism Description: This mutation is well known for its effects on proliferation and its association with AML and MPN, suggesting that this variant might have been involved in the TkI resistance of this patient.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-217 [14]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Chronic myelogenous Ph(+) leukemia [ICD-11: 2A20.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bcr/Abl-expressing k562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562DR cells; Blood; Homo sapiens (Human); CVCL_4V59
• In Vitro Model: K562NR cells; Blood; Homo sapiens (Human); CVCL_4V63
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Forced expression of miR-217 inhibited expression of DNMT3A through a miR-217-binding site within the 3'-untranslated region of DNMT3A and sensitized these cells to growth inhibition mediated by the TkI. long-term exposure of CML k562 cells to ABL TkI such as dasatinib and nilotinib decreased the levels of miR-217 and increased the levels of DNMT1 and DNMT3A, as well as resulting in acquisition of TkI resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [14]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Chronic myelogenous Ph(+) leukemia [ICD-11: 2A20.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bcr/Abl-expressing k562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562DR cells; Blood; Homo sapiens (Human); CVCL_4V59
• In Vitro Model: K562NR cells; Blood; Homo sapiens (Human); CVCL_4V63
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Forced expression of miR-217 inhibited expression of DNMT3A through a miR-217-binding site within the 3'-untranslated region of DNMT3A and sensitized these cells to growth inhibition mediated by the TkI. long-term exposure of CML k562 cells to ABL TkI such as dasatinib and nilotinib decreased the levels of miR-217 and increased the levels of DNMT1 and DNMT3A, as well as resulting in acquisition of TkI resistance.

Gastrointestinal cancer [ICD-11: 2B5B]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Molecule Alteration: Missense mutation; p.N655T
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene mutation analysis assay
• Experiment for Drug Resistance: Computed tomography assay
• Mechanism Description: According to gene mutation analysis, the resistant GIST contained not only the primary genetic kIT mutation in not only exon 11 but also secondary kIT mutation in exon 13 (Asn655Thr).

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Epidermal growth factor receptor (EGFR) [2]

• Molecule Alteration: Missense mutation; p.E711K
• Resistant Disease: HER2 positive breast cancer [ICD-11: 2C60.8]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Positron emission tomography/Computed tomography assay
• Mechanism Description: Seven genes, including epidermal growth factor receptor (EGFR), G protein subunit alpha S (GNAS), HRas proto-oncogene (HRAS), mutL homolog 1 (MLH1), cadherin 1 (CDH1), neuroblastoma RAS viral oncogene homolog (NRAS), and NOTCH1, that only occurred mutations in the resistant group were associated with the resistance of targeted therapy.

References

• Ref 1: CircBA9.3 supports the survival of leukaemic cells by up-regulating c-ABL1 or BCR-ABL1 protein levels. Blood Cells Mol Dis. 2018 Nov;73:38-44. doi: 10.1016/j.bcmd.2018.09.002. Epub 2018 Sep 14.
• Ref 2: Circulating-free DNA Mutation Associated with Response of Targeted Therapy in Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer. Chin Med J (Engl). 2017 Mar 5;130(5):522-529. doi: 10.4103/0366-6999.200542.
• Ref 3: Sequential development of mutant clones in an imatinib resistant chronic myeloid leukaemia patient following sequential treatment with multiple tyrosine kinase inhibitors: an emerging problem . Cancer Chemother Pharmacol. 2009 Jun;64(1):195-7. doi: 10.1007/s00280-008-0905-5. Epub 2009 Jan 21.
• Ref 4: Surgical resection of recurrent gastrointestinal stromal tumor after interruption of long-term nilotinib therapy. Surg Case Rep. 2016 Dec;2(1):137. doi: 10.1186/s40792-016-0266-y. Epub 2016 Nov 19.
• Ref 5: Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations. Blood. 2011 Mar 31;117(13):3641-7. doi: 10.1182/blood-2010-08-302679. Epub 2010 Dec 14.
• Ref 6: Use of direct sequencing for detection of mutations in the BCR-ABL kinase domain in Slovak patients with chronic myeloid leukemia. Neoplasma. 2011;58(6):548-53. doi: 10.4149/neo_2011_06_548.
• Ref 7: Analysis of mutations in the BCR-ABL1 kinase domain, using direct sequencing: detection of the T315I mutation in bone marrow CD34+ cells of a patient with chronic myelogenous leukemia 6 months prior to its emergence in peripheral blood. Mol Diagn Ther. 2012 Jun 1;16(3):163-6. doi: 10.2165/11632420-000000000-00000.
• Ref 8: Complexity of BCR-ABL kinase domain mutations during the course of therapy with tyrosine kinase inhibitors in chronic myeloid leukemia. Am J Hematol. 2009 Apr;84(4):256-7. doi: 10.1002/ajh.21366.
• Ref 9: Outcome of patients with chronic myeloid leukemia with multiple ABL1 kinase domain mutations receiving tyrosine kinase inhibitor therapy. Haematologica. 2011 Jun;96(6):918-21. doi: 10.3324/haematol.2010.039321. Epub 2011 Feb 28.
• Ref 10: Role of treatment in the appearance and selection of BCR-ABL1 kinase domain mutations. Mol Diagn Ther. 2012 Aug 1;16(4):251-9. doi: 10.1007/BF03262214.
• Ref 11: Three novel patient-derived BCR/ABL mutants show different sensitivity to second and third generation tyrosine kinase inhibitors. Am J Hematol. 2012 Nov;87(11):E125-8. doi: 10.1002/ajh.23338. Epub 2012 Oct 9.
• Ref 12: European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013 Aug 8;122(6):872-84. doi: 10.1182/blood-2013-05-501569. Epub 2013 Jun 26.
• Ref 13: Dissecting Genomic Aberrations in Myeloproliferative Neoplasms by Multiplex-PCR and Next Generation Sequencing. PLoS One. 2015 Apr 20;10(4):e0123476. doi: 10.1371/journal.pone.0123476. eCollection 2015.
• Ref 14: Downregulation of miR-217 correlates with resistance of Ph(+) leukemia cells to ABL tyrosine kinase inhibitors. Cancer Sci. 2014 Mar;105(3):297-307. doi: 10.1111/cas.12339. Epub 2014 Jan 30.