Role of BCR/ABL gene-expression levels in determining the phenotype and imatinib sensitivity of transformed human hematopoietic cells.
Increased levels of Bcr-Abl expression in chronic myelogenous leukemia (CML) cells are associated with disease progression and imatinib (IM) resistance. However, it is not clear if these associations are a direct result of elevated Bcr-Abl expression. We used a human transduction model of CML to directly investigate the role of varying Bcr-Abl expression levels in determining the phenotype and IM sensitivity of hematopoietic cells. CD34(+) cells were transduced with vectors coexpressing Bcr-Abl and GFP, and cells expressing low and high levels of GFP and Bcr-Abl (BA(lo) and BA(hi)) were selected. BA(hi) cells demonstrated enhanced activation of downstream proliferative and antiapoptotic signaling and enhanced proliferation and survival compared to BA(lo) cells. Freshly isolated BA(hi) CD34(+) cells and cell lines demonstrated increased IM-mediated growth inhibition likely reflecting Bcr-Abl dependence for growth and survival. CD34(+) cells expressing BCR/ABL kinase-mutant genes demonstrated resistance to IM-mediated inhibition of proliferation and viability, which was not enhanced by increased expression of BCR/ABL kinase-mutant genes. We conclude that Bcr-Abl overexpression results in increased proliferation and antiapoptotic signaling in CD34(+) cells, but may not play a direct role in IM resistance in progenitor cells expressing either wild-type or mutant BCR/ABL genes.
Modi
Hardik
H
Department of Hematopoietic Stem Cell and Leukemia Research, Division of Hematology and Hematopoietic Cell Transplantation (HCT), City of Hope National Medical Center, Duarte, CA 91010, USA.
McDonald
Tinisha
T
Chu
Su
S
Yee
Jiing-Kuan
JK
Forman
Stephen J
SJ
Bhatia
Ravi
R
D001549:Benzamides; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D000068877:Imatinib Mesylate; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014161:Transduction, Genetic
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl