Cancer cell · 2016
Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia.
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Wang Lili, Brooks Angela N, Fan Jean, Wan Youzhong, Gambe Rutendo, Li Shuqiang, Hergert Sarah, Yin Shanye, Freeman Samuel S, Levin Joshua Z, Fan Lin, Seiler Michael, Buonamici Silvia, Smith Peter G, Chau Kevin F, Cibulskis Carrie L, Zhang Wandi, Rassenti Laura Z, Ghia Emanuela M, Kipps Thomas J, Fernandes Stacey, Bloch Donald B, Kotliar Dylan, Landau Dan A, Shukla Sachet A, Aster Jon C, Reed Robin, DeLuca David S, Brown Jennifer R, Neuberg Donna, Getz Gad, Livak Kenneth J, Meyerson Matthew M, Kharchenko Peter V, Wu Catherine J
Аннотация
Mutations in SF3B1, which encodes a spliceosome component, are associated with poor outcome in chronic lymphocytic leukemia (CLL), but how these contribute to CLL progression remains poorly understood. We undertook a transcriptomic characterization of primary human CLL cells to identify transcripts and pathways affected by SF3B1 mutation. Splicing alterations, identified in the analysis of bulk cells, were confirmed in single SF3B1-mutated CLL cells and also found in cell lines ectopically expressing mutant SF3B1. SF3B1 mutation was found to dysregulate multiple cellular functions including DNA damage response, telomere maintenance, and Notch signaling (mediated through KLF8 upregulation, increased TERC and TERT expression, or altered splicing of DVL2 transcript, respectively). SF3B1 mutation leads to diverse changes in CLL-related pathways.