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A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion

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 senesce...

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Published in:Cancer cell 2019-02, Vol.35 (2), p.283-296.e5
Main Authors: Yin, Shanye, Gambe, Rutendo G., Sun, Jing, Martinez, Aina Zurita, Cartun, Zachary J., Regis, Fara Faye D., Wan, Youzhong, Fan, Jean, Brooks, Angela N., Herman, Sarah E.M., ten Hacken, Elisa, Taylor-Weiner, Amaro, Rassenti, Laura Z., Ghia, Emanuela M., Kipps, Thomas J., Obeng, Esther A., Cibulskis, Carrie L., Neuberg, Donna, Campagna, Dean R., Fleming, Mark D., Ebert, Benjamin L., Wiestner, Adrian, Leshchiner, Ignaty, DeCaprio, James A., Getz, Gad, Reed, Robin, Carrasco, Ruben D., Wu, Catherine J., Wang, Lili
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Language:English
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Summary: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. [Display omitted] •Sf3b1-K700E mutation impairs 3′ splice site selection and induces cellular senescence•Sf3b1-K700E mutation in combination with Atm deletion causes CLL•CLL cells show genome instability and dysregulated BCR signaling•Human CLL cells with SF3B1 mutations show dysregulation of BCR signaling Yin et al. show that Sf3b1-K700E mutation in mouse B cells induces cellular senescence, but deletion of Atm overcomes senescence and leads to the development of CLL-like disease. Both human and mouse CLL harboring mutant SF3B1 exhibit deregulated B cell receptor signaling and increased sensitivity to ibrutinib.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccell.2018.12.013