期刊
BLOOD
卷 109, 期 12, 页码 5411-5421出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2006-06-032490
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资金
- NCI NIH HHS [R01 CA95684, R01 CA095684] Funding Source: Medline
- NHLBI NIH HHS [R01 HL077847, R01 HL77847] Funding Source: Medline
Increased levels of Bcr-Abl expression in chronic myelogenous leukemia (CIVIL) 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 wildtype or mutant BCR/ABL genes.
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