The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells

CD49d and CD38 are independent negative prognostic markers in chronic lymphocytic leukemia (CLL). Their associated expression marks a disease subset with a highly aggressive clinical course. Here, we demonstrate a constitutive physical association between the CD49d/CD29 integrin complex and CD38 in primary CLL cells and B-cell lines by (i) cocapping, (ii) coimmunoprecipitation and (iii) cell adhesion experiments using CD49d-specific substrates (vascular-cell adhesion molecule-1 or CS-1/H89 fibronectin fragments). The role of CD38 in CD49d-mediated cell adhesion was studied in CD49d CD38 and CD49d + CD38 - primary CLL cells, and confirmed using CD38 transfectants of the originally CD49d + CD38 - CLL-derived cell line Mec-1. Results indicate that CD49d + CD38 - cells adhered more efficiently onto CD49d-specific substrates than CD49d CD38 cells (P0.001). Upon adhesion, CD49d + CD38 - cells underwent distinctive changes in cell shape and morphology, with higher levels of phosphorylated Vav-1 than CD49d + CD38 - cells (P0.0006) and a more complex distribution of F-actin to the adhesion sites. Lastly, adherent CD49d + CD38 - cells were more resistant to serum-deprivation- induced (P0.001) and spontaneous (P0.03) apoptosis than the CD49d + CD38 -s counterpart. Altogether, our results point to a direct role for CD38 in enhancing CD49d-mediated adhesion processes in CLL, thus providing an explanation for the negative clinical impact exerted by these molecules when coexpressed in neoplastic cells.