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

Abstract

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 þ CD38 À cells (P ¼ 0.0006) and a more complex distribution of F-actin to the adhesion sites. Lastly, adherent CD49d þ CD38 þ cells were more resistant to serum-deprivation-induced (Po0.001) and spontaneous (P ¼ 0.03) apoptosis than the CD49d þ CD38 À 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.

Trisomy 12 chronic lymphocytic leukemia cells exhibit upregulation of integrin signaling that is modulated by NOTCH1 mutations

“…This division is of functional importance as the a-integrin CD49d pairs with either of the b-integrins (CD29 or ITGB7) to form integrin dimers, and this forms a macromolecular cell surface complex with CD38, CD44, and matrix metalloproteinase 9 on CLL cells. 20,21 Importantly, these findings suggest that our results are not consistent with increased motility contributing to the adverse prognosis associated with NOTCH1 mutations, as differential b2-integrin expression was not associated with any LFA-1-mediated functional changes in our assays. It is possible that other functional effects may be important, and we hypothesize that NOTCH1-induced suppression of b2-integrin expression may allow escape from immune surveillance.…”

Clonal B-cell lymphocytosis exhibiting immunophenotypic features consistent with a marginal-zone origin: is this a distinct entity?

“…[27][28][29][30] In CLL, the CD49d/CD29 integrin complex is physically associated with CD38, being part of a macromolecular complex that impacts on migration and adhesion capacity, cell proliferation, and survival. 29,31,32 In this context, the dissociation of CD49d from CD38 expression in the present series (at least for the great majority of cases) is noteworthy, but it is unclear whether the observed phenotype reflects the cell of origin or the neoplastic process.…”

Molecular Pathways: Targeting the Microenvironment in Chronic Lymphocytic Leukemia—Focus on the B-Cell Receptor

“…Furthermore, CLL cells expressing high levels of the intracellular adaptor ZAP-70 (23), CD38 (24), or VLA-4 integrins (25) display higher migratory potential toward CXCL12. VLA-4 integrins cooperate with chemokine receptors and CD38 (26) in CLL cell adhesion to stromal cells (27). In addition, high CD38 (28) and VLA-4 (29) expression are also predictors of an inferior clinical outcome, supporting the notion that disease aggressiveness is linked to tissue homing and adhesion of CLL cells.…”