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

Abstract

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 A 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]

Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

“…37 Recently, it has been observed that CD49d was nearly universally expressed in trisomy 12 CLL patients. 36 In our study, we demonstrated a significant correlation between lower bax/bcl-2 ratio and trisomy 12 (Table 1), so suggesting that this ratio may represent a further mechanism of chemoresistance in this subset. A strict association was also observed between bax/bcl-2 negative patients and other high risk (del11q and del17p) classes (Table 1), thus confirming the clinical impact of the apoptotic mechanisms in these poor risk cytogenetic subsets.…”

“…It is well known that CD38 and CD49d overexpression are adverse prognostic markers in CLL 19,34,35 and it has been reported that interactions involving CD38 and CD49d prevent spontaneous and drug-induced apoptosis of normal and neoplastic B cells. 36 Interestingly, co-culture of CLL cells with human vascular endothelial cells determined a simultaneous overexpression of CD38, CD49d bax/bcl-2 ratio in CLL haematologica | 2016; 101(1) Figure 5. Progression-free survival (PFS) curves based on bax/bcl-2 within IGHV unmutated subgroup and TP53 mutated subgroup.…”

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

“…5 Purified CLL cells from five CD49d þ CD38 À and five CD49d þ CD38 þ cases (Supplementary Table S2) were cultured on VCAM-1, and cell viability determined at day 7. As expected, CD49d/VCAM-1 interaction protected from spontaneous apoptosis both CD49d þ CD38 þ (P ¼ 0.004) and CD49d þ CD38 À (P ¼ 0.001) CLL cells (data not shown).…”

“…6 --10,28,37 In this regard, we have previously described a pro-survival circuitry operating in the context of CD49d þ CD38 þ CLL bone marrow milieu, sequentially involving the CD38/CD31 pair, CCL3 and CCL4 with their receptors, and eventually pro-survival signals delivered through the CD49d/VCAM-1 axis. 5 Moreover, CD49d and CD38 have been linked together in a recent study demonstrating that coculture of CLL cells with endothelial cells determines a significant increase of CD49d and CD38 expression, and enhances CLL cell viability, these effects being mediated by activation of the NF-kB transcription factor Rel A. 38 The starting observation of the present study was that CD49d and CD38 along with CD44 and MMP-9 are physically associated on the membrane of CLL cells as part of a macromolecular complex.…”

“…16 --18 In CLL cells, CD49d and CD38 are functionally linked, through the production of specific soluble factors, in a circuitry regulating adhesion and survival of CD49d þ CD38 þ CLL. 5 Several studies demonstrated the propensity of CD38 to form supra-molecular complexes in various hematopoietic cell types. 19 --24 The reason of such physical interactions of CD38 is at least twofold.…”