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CD38/CD31, the CCL3 and CCL4 Chemokines, and CD49d/Vascular Cell Adhesion Molecule-1 Are Interchained by Sequential Events Sustaining Chronic Lymphocytic Leukemia Cell Survival

¹ Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy; ² Department of Human Pathology, University of Palermo, Palermo, Italy; ³ Department of Physics, University of Bologna, Bologna, Italy; ⁴ Department of Life Sciences, University of Trieste, Trieste, Italy; ⁵ Division of Hematology, Department of Clinical and Experimental Medicine and BRMA, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy; ⁶ Division of Hematology, S Eugenio Hospital and University of Tor Vergata, Rome, Italy; and ⁷ Laboratory of Immunogenetics, Department of Genetics, Biology and Biochemistry and CeRMS, University of Turin, Turin, Italy

Requests for reprints: Valter Gattei, Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, via Franco Gallini 2, Aviano PN, Italy. Phone: 0039-0434-659410; Fax: 0039-0434-659409; E-mail: vgattei{at}cro.it.

Key Words: CLL • integrins • chemokines • CD49d • CD38 • prognosis

CD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Despite evidence that both molecules are involved in interactions occurring between CLL and normal cells in the context of CLL-involved tissues, a functional link is still missing. Using gene expression profiles comparing CD38⁺CD49d⁺ versus CD38^–CD49d^– CLL cells, we showed overexpression of the CCL3 and CCL4 chemokines in cells from the former group. These chemokines were also up-regulated by CD38 signals in CLL; moreover, CCL3 was expressed by CLL cells from bone marrow biopsies (BMB) of CD38⁺CD49d⁺ but not CD38^–CD49d^– cases. High levels of CCR1 and, to a lesser extent, CCR5, the receptors for CCL3 and CCL4, were found in CLL-derived monocyte-macrophages. Consistently, CCL3 increased monocyte migration, and CD68⁺ macrophage infiltration was particularly high in BMB from CD38⁺CD49d⁺ CLL. Conditioned media from CCL3-stimulated macrophages induced endothelial cells to express vascular cell adhesion molecule-1 (VCAM-1), the CD49d ligand, likely through tumor necrosis factor overproduction. These effects were apparent in BMB from CD38⁺CD49d⁺ CLL, where lymphoid infiltrates were characterized by a prominent meshwork of VCAM-1⁺ stromal/endothelial cells. Lastly, CD49d engagement by VCAM-1 transfectants increased viability of CD38⁺CD49d⁺ CLL cells. Altogether, CD38 and CD49d can be thought of as parts of a consecutive chain of events ultimately leading to improved survival of CLL cells. [Cancer Res 2009;69(9):4001–9]