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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5411-5421. Prepublished online as a Blood First Edition Paper on March 8, 2007; DOI 10.1182/blood-2006-06-032490.
Submitted June 29, 2006
Dept of Hematopoietic Stem cell and Leukemia Research, 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.
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