Journal
MOLECULAR CANCER THERAPEUTICS
Volume 7, Issue 1, Pages 48-58Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-07-0042
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Chronic myelogenous leukemia (CML) is driven by constitutively activated Bcr-Abl tyrosine kinase, which causes the defective adhesion of CML cells to bone marrow stroma. The overexpression of p210(Bcr-Abl) was reported to down-regulate CXCR4 expression, and this is associated with the cell migration defects in CML. We proposed that tyrosine kinase inhibitors, imatinib or INNO-406, may restore CXCR4 expression and cause the migration of CML cells to bone marrow microenvironment niches, which in turn results in acquisition of stroma-mediated chemoresistance of CML progenitor cells. In KBM5 and K562 cells, imatinib, INNO-406, or IFN-alpha increased CXCR4 expression and migration. This increase in CXCR4 levels on CIVIL progenitor cells was likewise found in samples from CML patients treated with imatinib or IFN-alpha. Imatinib induced G(0)-G(1) cell cycle block in CML cells, which was further enhanced in a mesenchymal stem cell (MSC) coculture system. MSC coculture protected KBM-5 cells from imatinib-induced cell death. These antiapoptotic effects were abrogated by the CXCR4 antagonist AMD3465 or by inhibitor of integrin-linked kinase QLT0267. Altogether, these findings suggest that the upregulation of CXCR4 by imatinib promotes migration of CML cells to bone marrow stroma, causing the Go-G, cell cycle arrest and hence ensuring the survival of quiescent CML. progenitor cells.
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