SF3B1 mutation accelerates the development of CLL via activation of the mTOR pathway

RNA splicing factor SF3B1 is among the most recurrently mutated genes in chronic lymphocytic leukemia (CLL); these mutations frequently co-occur with chromosome 13q deletion (del(13q)). The presence of SF3B1 mutation and del(13q) is predictive of poorer prognosis in CLL, suggesting that these two lesions impact the aggressiveness of CLL. While del(13q) in murine B cells (Mdr mice), but not expression of Sf3b1-K700E, drives the initiation of CLL, we hypothesize that SF3B1 mutation accelerates CLL progression. In this study, we crossed mice with a B-cell-specific Sf3b1-K700E allele with Mdr mice to determine the impact of Sf3b1 mutation on CLL progression. We found that the co-occurrence of these two lesions in murine B cells indeed causes acceleration of CLL. We showed that Sf3b1-K700E impacts alternative RNA splicing of Nfatc1 and activates mTOR signaling and the MYC pathway, contributing to CLL acceleration. Moreover, concurrent inhibition of RNA splicing and mTOR pathways leads to cell death in vitro and in vivo in murine CLL cells with SF3B1 mutation and del(13q). Our results thus suggest that SF3B1 mutation contributes to the aggressiveness of CLL through the activation of the mTOR pathway, likely mediated by alternative splicing of Nfatc1, providing a rationale for targeting mTOR and RNA splicing in the subset of CLL patients with both SF3B1 mutations and del(13q).