Evidence for a macromolecular complex in poor prognosis CLL that contains CD38, CD49d, CD44 and MMP‐9

Abstract

Progressive chronic lymphocytic leukaemia is characterized by the accumulation of neoplastic B-cells in the tissues and correlates with the expression of prognostic biomarkers, such as CD38, CD49d and matrix metalloproteinase-9 (MMP9), which are involved in migration and tissue invasion. In this study we investigated the physical relationship between these molecules and demonstrated that CD38, CD49d, MMP9 and CD44 were physically associated in a supramolecular cell surface complex. Our findings provide a molecular basis for the correlation between expression of these proteins and prognosis and, as the complex is not present in normal B-cells, suggest a novel leukaemia-specific therapeutic target.

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

“…CD49d, the a4 integrin subunit, is critically implicated in microenvironmental interactions through the binding to fibronectin and vascular cell adhesion molecule-1. [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.…”

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

“…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. 28 Moving from these observations, here we investigated in detail the relationship between CD38 and the CD49d/CD29 integrin by: (i) cocapping experiments, a validated experimental procedure for disclosing membrane molecular complexes, 33 demonstrating a colocalization of CD38 in polar aggregates containing CD49d molecules; (ii) bidirectional immunoprecipitation experiments, providing evidence for an association between CD38 and the CD49d/CD29 integrin heterodimer, both inside and outside the cell membrane lipid rafts. The last finding suggests that the CD49d/CD29/CD38 complexes are free to shuttle in and out of these specialized cholesterol-enriched membrane microdomains, where signaling transduction is organized.…”

“…27 Recently, a cell surface macromolecular complex which includes CD38, CD49d, CD44 and MMP-9 has been found in poor prognosis CLL. 28 Here we investigated in detail the physical relationship between the CD49d/CD29 heterodimer and CD38 in CLL, and provided evidence that the resulting molecular complex enhances CD49d-mediated activities.…”

The progress of angiogenic factors in the development of leukemias

“…Serum MMP-9 not only can be likely to predict clinical outcome of patients with early CLL but also can help to refine the prognosis of CLL (70). In MDS, MMPs expression may produce a useful tool for diagnosis, prognosis and a possible target for clinical treatment.…”