ABSTRACT
SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its role in the pathogenesis of CLL remains elusive. Here, we show that conditional expression of Sf3b1-K700E mutation in mouse B cells disrupts pre-mRNA splicing, alters cell development, and induces a state of cellular senescence. Combination with Atm deletion leads to the overcoming of cellular senescence and the development of CLL-like disease in elderly mice. These CLL-like cells show genome instability and dysregulation of multiple CLL-associated cellular processes, including deregulated B cell receptor signaling, which we also identified in human CLL cases. Notably, human CLLs harboring SF3B1 mutations exhibit altered response to BTK inhibition. Our murine model of CLL thus provides insights into human CLL disease mechanisms and treatment.
Subject(s)
B-Lymphocytes/immunology , Cellular Senescence , Gene Deletion , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation , Neoplasms, Experimental/genetics , Phosphoproteins/genetics , RNA Splicing Factors/genetics , Receptors, Antigen, B-Cell/immunology , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase/metabolism , Alternative Splicing , Animals , Antineoplastic Agents/pharmacology , Ataxia Telangiectasia Mutated Proteins/deficiency , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , Cellular Senescence/drug effects , DNA Damage , Genetic Predisposition to Disease , Genomic Instability , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Mice, Mutant Strains , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/immunology , Neoplasms, Experimental/metabolism , Phenotype , Phosphoproteins/metabolism , Piperidines , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , RNA Splicing Factors/metabolism , Receptors, Antigen, B-Cell/metabolism , Signal Transduction , Tumor Cells, CulturedABSTRACT
Mutations in SF3B1, which encodes a spliceosome component, are associated with poor outcome in chronic lymphocytic leukemia (CLL), but how these contribute to CLL progression remains poorly understood. We undertook a transcriptomic characterization of primary human CLL cells to identify transcripts and pathways affected by SF3B1 mutation. Splicing alterations, identified in the analysis of bulk cells, were confirmed in single SF3B1-mutated CLL cells and also found in cell lines ectopically expressing mutant SF3B1. SF3B1 mutation was found to dysregulate multiple cellular functions including DNA damage response, telomere maintenance, and Notch signaling (mediated through KLF8 upregulation, increased TERC and TERT expression, or altered splicing of DVL2 transcript, respectively). SF3B1 mutation leads to diverse changes in CLL-related pathways.
