CD49d is overexpressed by trisomy 12 chronic lymphocytic leukemia cells: evidence for a methylation-dependent regulation mechanism

Abstract

Key Points CD49d, a negative prognosticator with a key role for microenvironmental interactions in CLL, is near universally expressed in trisomy 12 CLL. CD49d overexpression in trisomy 12 CLL is regulated by a methylation-dependent mechanism.

CD49d (ITGA4) expression is a predictor of time to first treatment in patients with chronic lymphocytic leukaemia and mutated IGHV status

“…Mechanistically, higher expression of CD49d ‐a subunit of the VLA‐4 integrin receptor‐ could enhance its binding to VCAM1. This differential homing pattern could in turn allow CD49d‐positive cells to easily populate proliferation centres located in lymph nodes and bone marrow, with a distinct, protective and prosurvival microenvironment (Herishanu et al , ; Zucchetto et al , ; Mertens & Stilgenbauer, ; Walsby et al , ). The correlation between CD49d and CD38 expression, a surface molecule also actively involved in leukaemic cells homing, points in the same direction (Zucchetto et al , , ; Buggins et al , ; Dal Bo et al , ).…”

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

“…The mechanisms underlying upregulation of integrin signaling in trisomy 12 remain unclear, although a recent report has implicated altered epigenetic regulation as a cause of increased CD49d expression. 6 The presence of an extra copy of chromosome 12 may affect gene expression, and it is notable that the genes encoding both RAP1B and ITGB7 are located on chromosome 12. However, the genes For personal use only.…”

“…4 The increased prevalence of trisomy 12 in these lymphomas is of particular interest in light of studies reporting increased expression of the a-integrins CD11a and CD49d on trisomy 12 CLL cells. 5,6 The heterodimeric integrins CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1), CD49d/CD29 (very late antigen-4 [VLA-4]), and CD49d/ITGB7 are cell surface transmembrane proteins involved in the inducible adhesion of leukocytes to vascular walls during the process of transendothelial migration from the bloodstream into the tissues. This process is particularly important in CLL as it allows the malignant cells to enter lymphoid organs where they receive growth and survival signals and are protected from chemotherapy by a network of interactions with the lymph node (LN) microenvironment.…”

Mutational status of IGHV is the most reliable prognostic marker in trisomy 12 chronic lymphocytic leukemia

“…Tiziana D'Agaro, 1 Michaela Cerri, 2 Annalisa Chiarenza, 3 Kari G. Chaffee, 4 Adalgisa Condoluci, 5 Giovanni D'Arena, 6 Michele Spina, 7 Francesco Zaja, 8 Gabriele Pozzato, 9 Francesco Di Raimondo, 3 Davide Rossi, 5 Giovanni Del Poeta, 10 …”