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Immature Leukemic CD34⁺CXCR4⁺ Cells from CML Patients Have Lower Integrin-Dependent Migration and Adhesion in Response to the Chemokine SDF-1

^a Hadassah University Hospital, Gene Therapy Institute. Jerusalem, Israel;
^b Hematology Institute, Sheba Medical Center, Tel Hashomer, Israel;
^c The Plastic Surgery Department, The Tel-Aviv Sourasky Medical Center, Israel;
^d Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel

Key Words. Chronic myeloid leukemia • SDF-1 • CXCR4 • Integrins

Correspondence: Amnon Peled, Ph.D., Hadassah University Hospital, Gene Therapy Institute, P.O. Box 12000 Jerusalem, Israel. Telephone: 972-2-6778780; Fax: 972-2-6430982; e-mail: peled{at}hadassah.org.il

Chronic myelogenous leukemia (CML), a malignant myeloproliferative disorder originating from a pluripotent stem cell expressing the bcr-abl oncogene, is characterized by abnormal release of the expanded, malignant stem cell clone from the bone marrow (BM) into the circulation. Moreover, immature CD34⁺ CML cells have lower adhesion to stromal cells and fibronectin as well as lower engraftment potential in severe combined immunedeficient (SCID) and nonobese diabetic (NOD)/SCID mice than normal CD34⁺ cells. We report in this study that leukemic Philadelphia chromosome-positive (Ph⁺)CD34⁺ cells from newly diagnosed CML patients that express the chemokine receptor CXCR4 migrate in response to stromal-derived factor-1 (SDF-1). However, normal Ph-CD34⁺CXCR4⁺ cells derived from the same patient have significantly higher migration levels toward SDF-1. In contrast to their transwell migration potential, the SDF-1-mediated integrin-dependent polarization and migration of the Ph⁺CD34⁺CXCR4⁺ cells through extracellular matrix-like gels were significantly lower than for normal cells. Concomitantly, binding of these cells to vascular cell adhesion molecule-1 or fibronectin, in the presence of SDF-1, was also substantially lower. These findings suggest a major role for SDF-1-mediated, integrin-dependent BM retention of Ph⁺CD34⁺ cells.

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