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

Shanye Yin, Rutendo G. Gambe, Jing Sun, Aina Zurita Martinez, Zachary J. Cartun, Fara Faye D. Regis, Youzhong Wan, Jean Fan, Angela N. Brooks, Sarah E.M. Herman, Elisa ten Hacken, Amaro Taylor-Weiner, Laura Z. Rassenti, Emanuela M. Ghia, Thomas J. Kipps, Esther A. Obeng, Carrie L. Cibulskis, Donna Neuberg, Dean R. Campagna, Mark D. FlemingBenjamin L. Ebert, Adrian Wiestner, Ignaty Leshchiner, James A. DeCaprio, Gad Getz, Robin Reed, Ruben D. Carrasco, Catherine J. Wu, Lili Wang

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)283-296.e5
JournalCancer Cell
Volume35
Issue number2
DOIs
StatePublished - Feb 11 2019
Externally publishedYes

Keywords

  • ATM
  • BCR signaling
  • CLL
  • murine model
  • SF3B1

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Fingerprint

Dive into the research topics of 'A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion'. Together they form a unique fingerprint.

Cite this