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Research Articles: Therapeutics, Targets, and Development

CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma and promotes survival of quiescent CML cells

Departments of ¹ Clinical Pathology and ² Transfusion Medicine and Stem Cell Regulation, Juntendo University School of Medicine, Tokyo, Japan; ³ Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, ⁴ Department of Leukemia, and ⁵ Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ⁶ Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan

Requests for reprints: Marina Konopleva, Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, Unit 448, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-7260; Fax: 713-794-4747. E-mail: mkonople{at}mdanderson.org

Abstract

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- increased CXCR4 expression and migration. This increase in CXCR4 levels on CML progenitor cells was likewise found in samples from CML patients treated with imatinib or IFN-. Imatinib induced G₀-G₁ 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 up-regulation of CXCR4 by imatinib promotes migration of CML cells to bone marrow stroma, causing the G₀-G₁ cell cycle arrest and hence ensuring the survival of quiescent CML progenitor cells. [Mol Cancer Ther 2008;7(1):48–58]

Grant support: Juntendo University Project Research Program (to L. Jin).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁷ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 1/18/07; revised 9/11/07; accepted 12/ 4/07.