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Cancer Cell DOI:10.1016/j.ccell.2018.12.013

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

Publication TypeJournal Article
Year of Publication2019
AuthorsYin, S, Gambe, RG, Sun, J, Martinez, AZurita, Cartun, ZJ, Regis, FFaye D, Wan, Y, Fan, J, Brooks, AN, Herman, SEM, Hacken, ETen, 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
JournalCancer Cell
Date Published2019 Jan 14
ISSN1878-3686
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.

DOI10.1016/j.ccell.2018.12.013
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/30712845?dopt=Abstract

Alternate JournalCancer Cell
PubMed ID30712845