CD38 modulates CXCR4-mediated signals and homing of chronic lymphocytic leukemia (CLL) cells. (133.5)

Abstract Human CD38 is a glycoprotein endowed with enzymatic and receptorial functions. Its engagement leads to activation/proliferation signals in T, B, NK and dendritic cells. In chronic lymphocytic leukemia (CLL) cells, CD38 drives proliferation and survival signals and its expression defines a subset of cells with higher migration and signaling ability in response to CXCL12, a critical chemokine in the re-circulation of leukemic cells from blood to lymphoid organs. The aim of this work is to define the role of CD38 in the regulation of CLL cell homing, an essential step in the maintenance and progression of the disease. Results indicate that i) CD38 signals stabilize early (ERK1/2 phosphorylation) and late (chemotaxis) functional responses to CXCL12. ii) The use of CLL clones with bimodal CD38 expression confirmed that the migrating population is CD38+. Furthermore, iii) de novo expression of CD38 using a lentiviral technique is followed by increased sensitivity to CXCL12 and ultimately chemotaxis. iv) In CLL cells, CD38 and CXCR4 are part of the same supra-molecular complex, that also includes the tetraspanin CD81 and the integrin CD49d. These results indicate that CD38 synergizes with the CXCR4 signaling pathway, through a specific molecular organization on CLL cells. The functional and physical association between CD38 and CXCR4 represents a novel mechanism in the regulation of neoplastic lymphocyte chemotaxis and homing and potentially a novel therapeutic target.