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A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion.
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.
Afiliação
  • Yin S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • Gambe RG; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Sun J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Martinez AZ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Cartun ZJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Regis FFD; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Wan Y; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Fan J; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
  • Brooks AN; University of California, Santa Cruz, CA, USA.
  • Herman SEM; Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Ten Hacken E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Taylor-Weiner A; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Rassenti LZ; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Ghia EM; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Kipps TJ; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Obeng EA; St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Cibulskis CL; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Neuberg D; Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Campagna DR; Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
  • Fleming MD; Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
  • Ebert BL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
  • Wiestner A; Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Leshchiner I; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • DeCaprio JA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Getz G; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Reed R; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • Carrasco RD; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Wu CJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: cwu@partners.org.
  • Wang L; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Systems Biology, Beckman Research Institute, City of Hope, Monrovia, CA, USA. Electronic address: lilwang@coh.org.
Cancer Cell ; 35(2): 283-296.e5, 2019 02 11.
Article em En | MEDLINE | ID: mdl-30712845
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.
Assuntos
Linfócitos B/imunologia; Senescência Celular; Deleção de Genes; Leucemia Linfocítica Crônica de Células B/genética; Mutação; Neoplasias Experimentais/genética; Fosfoproteínas/genética; Fatores de Processamento de RNA/genética; Receptores de Antígenos de Linfócitos B/imunologia; Adenina/análogos & derivados; Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores; Tirosina Quinase da Agamaglobulinemia/metabolismo; Processamento Alternativo; Animais; Antineoplásicos/farmacologia; Proteínas Mutadas de Ataxia Telangiectasia/deficiência; Proteínas Mutadas de Ataxia Telangiectasia/genética; Proteínas Mutadas de Ataxia Telangiectasia/metabolismo; Linfócitos B/efeitos dos fármacos; Linfócitos B/metabolismo; Senescência Celular/efeitos dos fármacos; Dano ao DNA; Predisposição Genética para Doença; Instabilidade Genômica; Humanos; Leucemia Linfocítica Crônica de Células B/tratamento farmacológico; Leucemia Linfocítica Crônica de Células B/imunologia; Leucemia Linfocítica Crônica de Células B/metabolismo; Camundongos da Linhagem 129; Camundongos Endogâmicos C57BL; Camundongos Knockout; Camundongos Mutantes; Neoplasias Experimentais/tratamento farmacológico; Neoplasias Experimentais/imunologia; Neoplasias Experimentais/metabolismo; Fenótipo; Fosfoproteínas/metabolismo; Piperidinas; Inibidores de Proteínas Quinases/farmacologia; Pirazóis/farmacologia; Pirimidinas/farmacologia; Fatores de Processamento de RNA/metabolismo; Receptores de Antígenos de Linfócitos B/metabolismo; Transdução de Sinais; Células Tumorais Cultivadas
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fosfoproteínas / Linfócitos B / Receptores de Antígenos de Linfócitos B / Leucemia Linfocítica Crônica de Células B / Senescência Celular / Deleção de Genes / Fatores de Processamento de RNA / Mutação / Neoplasias Experimentais Idioma: En Ano de publicação: 2019 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fosfoproteínas / Linfócitos B / Receptores de Antígenos de Linfócitos B / Leucemia Linfocítica Crônica de Células B / Senescência Celular / Deleção de Genes / Fatores de Processamento de RNA / Mutação / Neoplasias Experimentais Idioma: En Ano de publicação: 2019 Tipo de documento: Article