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

Abstract

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 immune-deficient (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.