Characterization and Manipulation of NZB miR15a/16-1 loci for CLL Therapy (46.50)

Abstract

Abstract Chronic Lymphocytic Leukemia (CLL) is a malignancy characterized by accumulation of mature CD5+ B-cells in peripheral lymphoid organs, bone marrow and 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 that is associated with a mutation and deletion in the miR15a/16-1 region. The NZB loci lead to a processing defect inhibiting the conversion of pri-miR15a/16-1 to pre-miR15a/16-1. We hypothesized that exogenously increasing its 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. 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 miR delivery. Based on our findings we propose that targeting BSAP could be used as a novel therapeutic strategy for B-CLL.