1. A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion
- Author
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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 EM, Hacken, Elisa ten, 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, and Wang, Lili
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Hematology ,Lymphoma ,Rare Diseases ,Lymphatic Research ,Genetics ,2.1 Biological and endogenous factors ,Adenine ,Agammaglobulinaemia Tyrosine Kinase ,Alternative Splicing ,Animals ,Antineoplastic Agents ,Ataxia Telangiectasia Mutated Proteins ,B-Lymphocytes ,Cellular Senescence ,DNA Damage ,Gene Deletion ,Genetic Predisposition to Disease ,Genomic Instability ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Mice ,129 Strain ,Mice ,Inbred C57BL ,Mice ,Knockout ,Mice ,Mutant Strains ,Mutation ,Neoplasms ,Experimental ,Phenotype ,Phosphoproteins ,Piperidines ,Protein Kinase Inhibitors ,Pyrazoles ,Pyrimidines ,RNA Splicing Factors ,Receptors ,Antigen ,B-Cell ,Signal Transduction ,Tumor Cells ,Cultured ,ATM ,BCR signaling ,CLL ,SF3B1 ,murine model ,Neurosciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - 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.
- Published
- 2019