Pro-apoptotic effect of increasing miR15a/16-1 expression by different strategies in B-CLL cells (165.28)

Abstract

Abstract Chronic Lymphocytic Leukemia (CLL) is a chronic lymphoid malignancy characterized by accumulation of mature CD5+ B-cells in peripheral lymphoid organs, bone marrow and peripheral blood and is incurable with conventional therapy. We have previously shown that similar to human B-CLL cells, NZB mice (de novo mouse model of CLL) have 50% less level of miR15a/16-1 (pro-apoptotic). We hypothesized that exogenously increasing their expression would lead to increased apoptosis in tumor cells. Using a lentiviral delivery system, we were able to stably increase the level of these two microRNAs in LNC (NZB derived B-CLL cell line). The apoptosis observed in miR-GFP transduced LNC was twice as much as in LNC transduced with GFP lentivirus (control). In addition to the miR defect, B-CLL cells have a very high level of B-cell specific activator protein (BSAP) and this prevents their terminal differentiation. Recent reports have suggested that BSAP and miR15a/16-1 form an autoregulatory loop. We found that the level of the two oncoproteins BSAP and c-Myb were reduced in the miR-GFP transduced cells as compared to the control. Alternatively, we found that the miR defect can also be corrected by knocking down BSAP (using RNAi) leading to a cell cycle arrest. The second strategy is clinically relevant, since developing a BSAP inhibitor is more feasible than systemic microRNA delivery. Based on our findings we propose that targeting BSAP could be used as a novel therapeutic strategy for B-CLL.