A genetic murine model of CLL based on B cell-restricted expression of Sf3b1 mutation and Atm deletion

The RNA splicing factor SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its functional role in the pathogenesis of this disease has not been firmly established. Here, we show that conditional expression of heterozygous Sf3b1-K700E mutation in mouse B lineage cells disrupts pre-mRNA splicing, alters B-cell development and function, and induces a state of cellular senescence. B-cell restricted expression of this mutation combined with Atm deletion led to the overcoming of cellular senescence, together with enhanced genome instability and the development of clonal B220+CD5+ CLL cells in elderly mice at low penetrance. Mice with CLL-like disease were found to have amplifications of chromosomes 15 and 17. Integrated transcriptome and proteome analysis of the CLL-like cells revealed coordinated dysregulation of multiple CLL-associated cellular processes. This included an unexpected signature of deregulated B-cell receptor (BCR) signaling, which we could also identify in SF3B1-mutated CLL samples from two independent patient cohorts. Notably, human CLLs harboring SF3B1 mutations exhibited greater sensitivity and altered response kinetics to BTK kinase ibrutinib. Our genetically faithful murine model of CLL thus reveals fresh insights regarding the impact of SF3B1 mutation on CLL pathogenesis and suggests a system for identifying vulnerabilities related to this mutation that can be further exploited for the treatment of CLLs with this common mutation. Overall design: RNA-seq of B cells from WT, Sf3b1 MT, Atm MT, DM and DM-CLL mice

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Yin S, Gambe RG, Sun J, Martinez AZ, Cartun ZJ, Regis FFD, Wan Y, Fan J, Brooks AN, Herman SEM, Ten Hacken E, Taylor-Weiner A, Rassenti LZ, Ghia EM, Kipps TJ, Obeng EA, Cibulskis CL, Neuberg D, Campagna DR, Fleming MD, Ebert BL, Wiestner A, Leshchiner I, DeCaprio JA, Getz G, Reed R, Carrasco RD, Wu CJ, Wang L