Chemokine Receptors and Stromal Cells in the Homing and Homeostasis of Chronic Lymphocytic Leukemia B Cells

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Abstract
Chronic lymphocytic leukemia (CLL) is a disease characterized by an accumulation, of mature, functionally incompetent B lymphocytes in the blood, secondary lymphoid tissues, and marrow. Lymphocyte trafficking and homing to specialized microenvironments is an active process that depends on the sequential engagement of adhesion molecules and activation through chemokine receptors. CLL B cells express functional CXCR3, CXCR4, and CXCR5 chemokine receptors that can direct leukemia cell chemotaxis in vitro. Marrow stromal cells, blood-derived "nurse-like cells", and extramedullary stromal cells of mesenchymal origin secrete high amounts of stromal cell-derived factor-1 (SDF-1) and thereby can attract CLL B cells via CXCR4. In vitro, CLL cells are rescued from apoptosis by cell-cell contact with such cells. Moreover, we found that the capacity of these cells to protect leukemia cells from apoptosis in vitro is mediated, at least in part, by the SDF-1 chemokine. Taken together, these findings suggest that chemokines and their receptors on CLL B cells can govern the homing and survival of leukemia B cells in vivo and therefore may contribute to their noted resistance to chemotherapy-induced apoptosis. Conceivably, CXCR4, and possibly other chemokine receptors, may represent a novel target for the development of effective treatment of this disease.