| Literature DB >> 30712845 |
Shanye Yin1, Rutendo G Gambe2, Jing Sun2, Aina Zurita Martinez3, Zachary J Cartun2, Fara Faye D Regis2, Youzhong Wan2, Jean Fan4, Angela N Brooks5, Sarah E M Herman6, Elisa Ten Hacken2, Amaro Taylor-Weiner3, Laura Z Rassenti7, Emanuela M Ghia7, Thomas J Kipps7, Esther A Obeng8, Carrie L Cibulskis3, Donna Neuberg9, Dean R Campagna10, Mark D Fleming10, Benjamin L Ebert11, Adrian Wiestner6, Ignaty Leshchiner3, James A DeCaprio2, Gad Getz3, Robin Reed12, Ruben D Carrasco13, Catherine J Wu14, Lili Wang15.
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.Entities:
Keywords: ATM; BCR signaling; CLL; SF3B1; murine model
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Year: 2019 PMID： 30712845 PMCID： PMC6372356 DOI： 10.1016/j.ccell.2018.12.013
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743