Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells

Chemokines play a central role for lymphocyte trafficking and homing. The m echanisms that direct the tissue localization of B cells from patients with chronic lymphocytic leukemia (B-CLL) are unknown. We found that CLL B cell s express functional CXCR4 receptors for the chemokine stromal cell-derived factor-1 (SDF-1), as demonstrated by receptor endocytosis, calcium mobiliz ation, and actin polymerization;ion assays. Moreover, CLL B cells displayed chemotaxis to this chemokine that could be inhibited by monoclonal antibod ies (MoAbs) against CXCR4, pertussis toxin. or Wortmannin, a phosphatidylin ositol 3-kinase inhibitor. That this chemotaxis may be involved in the homi ng of CLL cells is argued by studies in which CLL B cells were cocultured w ith a murine marrow stromal cell line that secretes SDF-1. Within 2 hours, CLL B cells spontaneously migrated beneath such stromal cells in vitro (pse udoemperipolesis). This migration could be inhibited by pretreatment of CLL B cells with anti-CXCR4 MoAbs, SDF-1 alpha, or pertussis-toxin. Furthermor e, we noted strong downmodulation of CXCR4 on CLL B cells that migrated int o the stromal cell layer. These findings demonstrate that the chemokine rec eptor CXCR4 on CLL B cells plays a critical role for heterotypic adherence to marrow stromal cells and provide a new mechanism to account for the marr ow infiltration by neoplastic B cells. (C) 1999 by The American Society of Hematology.