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

CD49d is a negative prognosticator in chronic lymphocytic leukemia (CLL), expressed by ~40% of CLL cases and associated with aggressive, accelerated clinical courses. In this study, analyzing CD49d expression in a wide CLL cohort (n = 1200) belonging to different cytogenetic groups, we report that trisomy 12 CLL almost universally expressed CD49d and were characterized by the highest CD49d expression levels among all CD49d⁺ CLL. Through bisulfite genomic sequencing, we demonstrated that, although CD49d⁺/ trisomy 12 CLL almost completely lacked methylation of the CD49d gene, CD49d^–/no trisomy 12 CLL were overall methylated, the methylation levels correlating inversely to CD49d expression (P = .0001). Consistently, CD49d expression was recovered in CD49d^– hyper-methylated CLL cells upon in vitro treatment with the hypomethylating agent 5-aza-29-deoxycytidine. This may help explain the clinicobiological features of trisomy 12 CLL, including the high rates of cell proliferation and disease progression, lymph node involvement, and predisposition to Richter syndrome transformation.