In contrast to high CD49d, low CXCR4 expression indicates the dependency of chronic lymphocytic leukemia (CLL) cells on the microenvironment

Abstract

CD49d and CXCR4 are key determinants of interactions between chronic lymphocytic leukemia (CLL) tumor cells and their microenvironment. In this study, we investigated the effect of CD49d and CXCR4 expressions on survival of CLL cells. Primary CLL cells were cultured with CD49d ligand, VCAM-1, or bone marrow stromal cells (BMSCs); then, apoptosis and immunophenotype analyses were performed. VCAM-1 treatment could not induce direct apoptosis protection or immunophenotype change on the CD49d-expressing CLL cells, but resulted in actin reorganization. The BMSC-induced apoptosis protection was independent from the presence of CD49d expression of CLL cells, but showed an inverse correlation with their CXCR4 expression level. We suppose that CD49d contributes to enhanced survival of leukemic cells by mediating migration to the protective microenvironment, not by direct prevention of apoptosis. Moreover, CLL cells with low CXCR4 expression represent a subpopulation that is more dependent on the microenvironmental stimuli for survival, and show increased "death by neglect" when separated from the supportive niche.

The prognostic impact of CD49d protein and mRNA expression in patients with chronic lymphocytic leukaemia

“…The monoclonal humanised IgG4 anti-CD49d antibody -natalizumab -demonstrated the potential to overcome stromal cell-induced resistance of B cell lymphoma cells against rituximab and cytotoxic drugs in vitro [9,32]. CD49d playing a key role in adhesion and migration of cells and is related with BCR signalling by inside-out activation [10]. To date, the BCR signalling pathway has emerged as one of the most important targets for novel therapies in CLL using BCR kinase inhibitors, such as ibrutinib [33].…”

“…Recent studies have pointed to the surface adhesion molecule CD49d as one of the strongest of the poor prognostic factors in CLL [7,8]. CD49d -the α chain of the α 4 β 1 integrin heterodimer, also known as very late antigen 4 (VLA-4), coded by the ITGA4 gene -is involved in forming supportive microenvironmental interactions of CLL cells and accessory cells such as nurse-like cells, vascular endothelial cells, dendritic cells, and T cells [9,10]. Functionally, by binding to fibronectin and vascular-cell adhesion molecule-1 (VCAM-1), CD49d mediates cell-cell and cell-matrix interactions.…”

“…CD49d plays crucial roles in leucocyte trafficking, activation, and survival. It also mediates interactions between leucocytes and stromal cells of marrow or the germinal centre of lymphoid follicles [10][11][12][13][14]. Additionally, CD49d promotes B-cell survival via upregulation of Bcl-2 family members, which may determine progression of CLL [14].…”

“…This study aims to contribute to this knowledge by studying the expressions of CD49d protein and mRNA in a cohort of newly diagnosed Polish CLL patients. To distinguish between CD49d-positive and -negative patients when testing the prognostic impact of CD49d protein, most previous studies have recommended the cut-off of 30% of positive cells [7,8,10,19]. As benchmarks, we used the most common currently available prognostic factors in CLL: ZAP-70, CD38, IGHV gene mutational status, and IGHV subsets; and new mutations, such as NOTCH1, SF3B1 (splicing factor 3B subunit 1), and MYD88 (myeloid differentiation primary response gene 88).…”

Shared genomic segment analysis in a large high-risk chronic lymphocytic leukemia pedigree implicates CXCR4 in inherited risk

“…The 5' UTR of CXCR4 has been shown to be recurrently mutated in CLL [36] and has been found as a proto-onco fusion gene with MAML2 [37] . It been additionally been shown to be a key molecule in CLL cell trafficking into and out of the bone marrow [38] , referred to as "CXCR4-mediated migration", and influential in dependencies with the microenvironment [39] . Given its vital function in CLL proliferation, targeting CXCR4 in CLL has shown efficacy in treating the disease as well as modifying drug-response, particularly with the drug ibrutinib [40][41][42][43][44][45] .…”