Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.5436
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dc.titleThe BIM deletion polymorphism: A paradigm of a permissive interaction between germline and acquired TKI resistance factors in chronic myeloid leukemia
dc.contributor.authorKo T.K.
dc.contributor.authorChin H.S.
dc.contributor.authorChuah C.T.H.
dc.contributor.authorHuang J.W.J.
dc.contributor.authorNg K.-P.
dc.contributor.authorKhaw S.L.
dc.contributor.authorHuang D.C.S.
dc.contributor.authorOng S.T.
dc.date.accessioned2020-09-03T10:32:26Z
dc.date.available2020-09-03T10:32:26Z
dc.date.issued2016
dc.identifier.citationKo T.K., Chin H.S., Chuah C.T.H., Huang J.W.J., Ng K.-P., Khaw S.L., Huang D.C.S., Ong S.T. (2016). The BIM deletion polymorphism: A paradigm of a permissive interaction between germline and acquired TKI resistance factors in chronic myeloid leukemia. Oncotarget 7 (3) : 2721-2733. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.5436
dc.identifier.issn19492553
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/174113
dc.description.abstractBoth germline polymorphisms and tumor-specific genetic alterations can determine the response of a cancer to a given therapy. We previously reported a germline deletion polymorphism in the BIM gene that was sufficient to mediate intrinsic resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML), as well as other cancers [1]. The deletion polymorphism favored the generation of BIM splice forms lacking the pro-apoptotic BH3 domain, conferring a relative resistance to the TKI imatinib (IM). However, CML patients with the BIM deletion polymorphism developed both partial and complete IM resistance. To understand the mechanisms underlying the latter, we grew CML cells either with or without the BIM deletion polymorphism in increasing IM concentrations. Under these conditions, the BIM deletion polymorphism enhanced the emergence of populations with complete IM resistance, mimicking the situation in patients. Importantly, the combined use of TKIs with the BH3 mimetic ABT-737 overcame the BCR-ABL1-dependent and -independent resistance mechanisms found in these cells. Our results illustrate the interplay between germline and acquired genetic factors in confering TKI resistance, and suggest a therapeutic strategy for patients with complete TKI resistance associated with the BIM deletion polymorphism.
dc.sourceUnpaywall 20200831
dc.subject4 [4 (4' chloro 2 biphenylylmethyl) 1 piperazinyl] n [4 [3 dimethylamino 1 (phenylthiomethyl)propylamino] 3 nitrobenzenesulfonyl]benzamide
dc.subjectBIM protein
dc.subjectimatinib
dc.subject4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
dc.subjectABT-737
dc.subjectapoptosis regulatory protein
dc.subjectBCR ABL protein
dc.subjectBCR-ABL1 fusion protein, human
dc.subjectBIM protein
dc.subjectbiphenyl derivative
dc.subjectdasatinib
dc.subjectimatinib
dc.subjectmembrane protein
dc.subjectnitrophenol
dc.subjectoncoprotein
dc.subjectpiperazine derivative
dc.subjectprotein kinase inhibitor
dc.subjectpyrimidine derivative
dc.subjectsulfonamide
dc.subjectantineoplastic activity
dc.subjectapoptosis
dc.subjectArticle
dc.subjectBCR ABL1 gene
dc.subjectBIM gene
dc.subjectcancer resistance
dc.subjectcell growth
dc.subjectchronic myeloid leukemia
dc.subjectconcentration response
dc.subjectcontrolled study
dc.subjectdrug mechanism
dc.subjectgene
dc.subjectgene deletion
dc.subjectgenetic polymorphism
dc.subjecthuman
dc.subjecthuman cell
dc.subjectmyeloid leukemia cell line
dc.subjectdrug effects
dc.subjectgene deletion
dc.subjectgenetic polymorphism
dc.subjectgenetics
dc.subjectLeukemia, Myelogenous, Chronic, BCR-ABL Positive
dc.subjecttumor cell line
dc.subjectApoptosis
dc.subjectApoptosis Regulatory Proteins
dc.subjectBcl-2-Like Protein 11
dc.subjectBiphenyl Compounds
dc.subjectCell Line, Tumor
dc.subjectDasatinib
dc.subjectFusion Proteins, bcr-abl
dc.subjectGene Deletion
dc.subjectHumans
dc.subjectImatinib Mesylate
dc.subjectLeukemia, Myelogenous, Chronic, BCR-ABL Positive
dc.subjectMembrane Proteins
dc.subjectNitrophenols
dc.subjectPiperazines
dc.subjectPolymorphism, Genetic
dc.subjectProtein Kinase Inhibitors
dc.subjectProto-Oncogene Proteins
dc.subjectPyrimidines
dc.subjectSulfonamides
dc.typeArticle
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.doi10.18632/oncotarget.5436
dc.description.sourcetitleOncotarget
dc.description.volume7
dc.description.issue3
dc.description.page2721-2733
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