Abstract 389: CD38 is part of a network of molecules regulating chemotaxis and homing of CLL cells
Authors: Vaisitti Tiziana , Bologna Cinzia , Serra Sara , Rossi Davide , D'arena Giovanni , Laurenti Luca , Gottardi Daniela , Gaidano Gianluca , Malavasi Fabio , Deaglio Silvia 
Published: June 2012

Abstract
An essential step in the maintenance and progression of chronic lymphocytic leukemia (CLL) is the recirculation of leukemic cells from blood to favorable growth niches in the lymphoid organs. This process is regulated by an intricate network of signals, including chemokines and their receptors, adhesion molecules and proteases that digest the extracellular matrix. The CXCL12/CXCR4 axis is believed to play an essential role in the regulation of the homing process, re-directing CLL cells to BM and LN. The CD49d integrin mediates adhesion to other cells or to the extracellular matrix via VCAM-1 or CS-1 fibronectin fragment. Lastly, the extra-vasation step is mainly controlled by MMP-9, the only gelatinases expressed by CLL cells. The working hypothesis is that CD38 may be involved in these three aspects of leukocyte homing, through a physical and functional association with CXCR4, CD49d and MMP-9. CLL cells from a molecularly and clinically characterized cohort of patients were used. Functional responses to CXCL12 were studied by immunoblot and chemotaxis. Genetic manipulation of CLL cells was carried out using a lentiviral techinique. The activity of MMP-9 in CLL cells was analyzed by gelatin zymography. Results indicate that CD38 expression marks i) CLL cells that are highly sensitive to the actions of the CXCL12. Furthermore, ii) CD38+ cases are characterized by a higher expression and activity of MMP-9. Moreover, iii) the analysis of CLL patients with a bimodal expression of CD38 indicates that the CD38+ fraction of the clone is characterized by higher levels of MMP-9 compared to the negative one. These data suggest that the CD38+ component of a CLL clone is enriched in cells that have the molecular machinery to migrate from the blood to the lymphoid organs. A formal proof of the role played by CD38 was obtained using a lentiviral technique that allows genetic modification of freshly purified CLL cells. De novo expression of CD38 was followed by an increased sensitivity to the CXCL12 chemokine as well as by secretion of high amounts of the active form of MMP-9, suggesting that de novo CD38+ cells digest extracellular matrix more readily compared to the same cells infected with an empty virus. Finally, the engagement of CD38 by means of agonistic mAbs was followed by increased chemotaxis and MMP-9 activation, while blocking anti-CD38 mAbs were highly effective in preventing CLL homing in an in vivo mouse model. Finally, v) CD38 appears to co-localize with CXCR4 and MMP-9 in the same membrane areas, as inferred by confocal microscopy analysis. These results suggest that CD38 is part of a complex network of molecules/signals that fine tune homing of leukemic cells to growth-permissive microenvironment. The physical proximity of these molecules on CLL membrane indicate that they could form a large supramolecular complex with the characteristic of the invadosome, linking the ability to migrate and invade to the poor clinical outcome of these patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 389. doi:10.1158/1538-7445.AM2011-389