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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE122668 | GEO | 2018/11/20

REPOSITORIES: GEO

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Chronic Lymphocytic Leukemia MEC1 SF3B1 K700E and Wild Type Cell Lines' RNA-seq after Treatment with H3B-8800 Splicing Modulator.

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RNA sequencing of bone marrow CD34+ cells from myelodysplastic syndrome patients with and without SF3B1 mutation and from healthy controls

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2014-11-22 | E-GEOD-63569 | biostudies-arrayexpress

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Gene expression data from chronic lymphocytic leukemia samples

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2011-06-01 | E-GEOD-29605 | biostudies-arrayexpress

Cancer-Causing Mutations in SF3B1 Alter Splicing by Disrupting Interaction with SUGP1

Project description:SF3B1, which encodes an essential spliceosomal protein, is frequently mutated in myelodysplastic syndromes (MDS) and many cancers. However, the defect of mutant SF3B1 is unknown. Here, we analyzed RNA-sequencing data from MDS patients and confirmed that SF3B1 mutants use aberrant 3' splice sites. To elucidate the underlying mechanism, we purified complexes containing either wild-type or the hotspot K700E mutant SF3B1, and found that levels of a poorly studied spliceosomal protein, SUGP1, were reduced in mutant spliceosomes. Strikingly, SUGP1 knockdown completely recapitulated the splicing errors, whereas SUGP1 overexpression drove the protein, which our data suggests plays an important role in branchsite recognition, into the mutant spliceosome and partially rescued splicing. Other hotspot SF3B1 mutants showed similar altered splicing and diminished interaction with SUGP1. Our study demonstrates that SUGP1 loss is the sole defect of mutant SF3B1 spliceosomes and, since this defect can be rescued, suggests possibilities for therapeutic intervention.

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