Submitted June 29, 2006
Accepted March 3, 2007
Role of BCR/ABL gene expression levels in determining the phenotype and imatinib sensitivity of transformed human hematopoietic cells
Hardik Modi, Tinisha McDonald, Su Chu, Jiing-Kuan Yee, Stephen J. Forman, and Ravi Bhatia*
Dept of Hematopoietic Stem cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA, United States
Division of Virology Research, City of Hope National Medical Center, Duarte, CA, United States
Division of Hematology and HCT, City of Hope National Medical Center, Duarte, CA, United States
* Corresponding author; email: rbhatia{at}coh.org.
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 (BAlo and BAhi) were selected. BAhi cells demonstrated enhanced activation of downstream proliferative and anti-apoptotic signaling and enhanced proliferation and survival compared with BAlo cells. Freshly isolated BAhi 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 anti-apoptotic 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.
