NEOPLASIA

characterized by widespread involve-ment of the bone marrow at the time of diagnosis, implying continuous homing of WM cells into the marrow. The mecha-nisms by which trafficking of the malig-nant cells into the bone marrow has not been previously elucidated. In this study, we show that WM cells express high levels of chemokine and adhesion recep-tors, including CXCR4 and VLA-4. We showed that CXCR4 was essential for the migration and trans-endothelial migra-tion of WM cells under static and dynamic shear flow conditions, with significant inhibition of migration using CXCR4 knockdown or the CXCR4 inhibitor AMD3100. Similarly, CXCR4 or VLA-4 inhi-bition led to significant inhibition of adhe-sion to fibronectin, stromal cells, and endothelial cells. Decreased adhesion of WM cells to stromal cells by AMD3100 led to increased sensitivity of these cells to cytotoxicity by bortezomib. To further in-vestigate the mechanisms of CXCR4-dependent adhesion, we showed that CXCR4 and VLA-4 directly interact in re-sponse to SDF-1, we further investigated downstream signaling pathways regulat-ing migration and adhesion in WM. To-gether, these studies demonstrate that the CXCR4/SDF-1 axis interacts with VLA-4 in regulating migration and adhe-sion of WM cells in the bone marrow microenvironment. (Blood. 2008;112: 150-158