Please use this identifier to cite or link to this item:
https://doi.org/10.18632/oncotarget.5436
DC Field | Value | |
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dc.title | The BIM deletion polymorphism: A paradigm of a permissive interaction between germline and acquired TKI resistance factors in chronic myeloid leukemia | |
dc.contributor.author | Ko T.K. | |
dc.contributor.author | Chin H.S. | |
dc.contributor.author | Chuah C.T.H. | |
dc.contributor.author | Huang J.W.J. | |
dc.contributor.author | Ng K.-P. | |
dc.contributor.author | Khaw S.L. | |
dc.contributor.author | Huang D.C.S. | |
dc.contributor.author | Ong S.T. | |
dc.date.accessioned | 2020-09-03T10:32:26Z | |
dc.date.available | 2020-09-03T10:32:26Z | |
dc.date.issued | 2016 | |
dc.identifier.citation | Ko 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.issn | 19492553 | |
dc.identifier.uri | https://scholarbank.nus.edu.sg/handle/10635/174113 | |
dc.description.abstract | Both 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.source | Unpaywall 20200831 | |
dc.subject | 4 [4 (4' chloro 2 biphenylylmethyl) 1 piperazinyl] n [4 [3 dimethylamino 1 (phenylthiomethyl)propylamino] 3 nitrobenzenesulfonyl]benzamide | |
dc.subject | BIM protein | |
dc.subject | imatinib | |
dc.subject | 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide | |
dc.subject | ABT-737 | |
dc.subject | apoptosis regulatory protein | |
dc.subject | BCR ABL protein | |
dc.subject | BCR-ABL1 fusion protein, human | |
dc.subject | BIM protein | |
dc.subject | biphenyl derivative | |
dc.subject | dasatinib | |
dc.subject | imatinib | |
dc.subject | membrane protein | |
dc.subject | nitrophenol | |
dc.subject | oncoprotein | |
dc.subject | piperazine derivative | |
dc.subject | protein kinase inhibitor | |
dc.subject | pyrimidine derivative | |
dc.subject | sulfonamide | |
dc.subject | antineoplastic activity | |
dc.subject | apoptosis | |
dc.subject | Article | |
dc.subject | BCR ABL1 gene | |
dc.subject | BIM gene | |
dc.subject | cancer resistance | |
dc.subject | cell growth | |
dc.subject | chronic myeloid leukemia | |
dc.subject | concentration response | |
dc.subject | controlled study | |
dc.subject | drug mechanism | |
dc.subject | gene | |
dc.subject | gene deletion | |
dc.subject | genetic polymorphism | |
dc.subject | human | |
dc.subject | human cell | |
dc.subject | myeloid leukemia cell line | |
dc.subject | drug effects | |
dc.subject | gene deletion | |
dc.subject | genetic polymorphism | |
dc.subject | genetics | |
dc.subject | Leukemia, Myelogenous, Chronic, BCR-ABL Positive | |
dc.subject | tumor cell line | |
dc.subject | Apoptosis | |
dc.subject | Apoptosis Regulatory Proteins | |
dc.subject | Bcl-2-Like Protein 11 | |
dc.subject | Biphenyl Compounds | |
dc.subject | Cell Line, Tumor | |
dc.subject | Dasatinib | |
dc.subject | Fusion Proteins, bcr-abl | |
dc.subject | Gene Deletion | |
dc.subject | Humans | |
dc.subject | Imatinib Mesylate | |
dc.subject | Leukemia, Myelogenous, Chronic, BCR-ABL Positive | |
dc.subject | Membrane Proteins | |
dc.subject | Nitrophenols | |
dc.subject | Piperazines | |
dc.subject | Polymorphism, Genetic | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Proto-Oncogene Proteins | |
dc.subject | Pyrimidines | |
dc.subject | Sulfonamides | |
dc.type | Article | |
dc.contributor.department | DUKE-NUS MEDICAL SCHOOL | |
dc.description.doi | 10.18632/oncotarget.5436 | |
dc.description.sourcetitle | Oncotarget | |
dc.description.volume | 7 | |
dc.description.issue | 3 | |
dc.description.page | 2721-2733 | |
Appears in Collections: | Elements Staff Publications |
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