Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.5436
Title: The BIM deletion polymorphism: A paradigm of a permissive interaction between germline and acquired TKI resistance factors in chronic myeloid leukemia
Authors: 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.
Keywords: 4 [4 (4' chloro 2 biphenylylmethyl) 1 piperazinyl] n [4 [3 dimethylamino 1 (phenylthiomethyl)propylamino] 3 nitrobenzenesulfonyl]benzamide
BIM protein
imatinib
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
ABT-737
apoptosis regulatory protein
BCR ABL protein
BCR-ABL1 fusion protein, human
BIM protein
biphenyl derivative
dasatinib
imatinib
membrane protein
nitrophenol
oncoprotein
piperazine derivative
protein kinase inhibitor
pyrimidine derivative
sulfonamide
antineoplastic activity
apoptosis
Article
BCR ABL1 gene
BIM gene
cancer resistance
cell growth
chronic myeloid leukemia
concentration response
controlled study
drug mechanism
gene
gene deletion
genetic polymorphism
human
human cell
myeloid leukemia cell line
drug effects
gene deletion
genetic polymorphism
genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
tumor cell line
Apoptosis
Apoptosis Regulatory Proteins
Bcl-2-Like Protein 11
Biphenyl Compounds
Cell Line, Tumor
Dasatinib
Fusion Proteins, bcr-abl
Gene Deletion
Humans
Imatinib Mesylate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Membrane Proteins
Nitrophenols
Piperazines
Polymorphism, Genetic
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyrimidines
Sulfonamides
Issue Date: 2016
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
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.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/174113
ISSN: 19492553
DOI: 10.18632/oncotarget.5436
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