Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia

Lili Wang; Angela N Brooks; Jean Fan; Youzhong Wan; Rutendo Gambe; Shuqiang Li; Sarah Hergert; Shanye Yin; Samuel S Freeman; Joshua Z Levin; Lin Fan; Michael Seiler; Silvia Buonamici; Peter G Smith; Kevin F Chau; Carrie L Cibulskis; Wandi Zhang; Laura Z Rassenti; Emanuela M Ghia; Thomas J Kipps; Stacey Fernandes; Donald B Bloch; Dylan Kotliar; Dan A Landau; Sachet A Shukla; Jon C Aster; Robin Reed; David S DeLuca; Jennifer R Brown; Donna Neuberg; Gad Getz; Kenneth J Livak; Matthew M Meyerson; Peter V Kharchenko; Catherine J Wu

doi:10.1016/j.ccell.2016.10.005

Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia

Cancer Cell. 2016 Nov 14;30(5):750-763. doi: 10.1016/j.ccell.2016.10.005. Epub 2016 Nov 3.

Authors

Lili Wang¹, Angela N Brooks², Jean Fan³, Youzhong Wan⁴, Rutendo Gambe⁵, Shuqiang Li⁶, Sarah Hergert⁵, Shanye Yin⁷, Samuel S Freeman⁸, Joshua Z Levin⁸, Lin Fan⁸, Michael Seiler⁹, Silvia Buonamici⁹, Peter G Smith⁹, Kevin F Chau¹⁰, Carrie L Cibulskis⁸, Wandi Zhang⁵, Laura Z Rassenti¹¹, Emanuela M Ghia¹¹, Thomas J Kipps¹¹, Stacey Fernandes⁵, Donald B Bloch¹², Dylan Kotliar¹⁰, Dan A Landau¹, Sachet A Shukla⁵, Jon C Aster¹³, Robin Reed⁷, David S DeLuca⁸, Jennifer R Brown¹⁴, Donna Neuberg¹⁵, Gad Getz⁸, Kenneth J Livak⁶, Matthew M Meyerson⁵, Peter V Kharchenko³, Catherine J Wu¹⁶

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA; University of California, Santa Cruz, CA 95064, USA.
³ Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA; National Engineering Laboratory of AIDS Vaccine, School of Life Science, Jilin University, Changchun, Jilin, PRC.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA.
⁶ Fluidigm Corporation, South San Francisco, CA 94080, USA.
⁷ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
⁹ H3 Biomedicine, Cambridge, MA 02141, USA.
¹⁰ Harvard Medical School, Boston, MA 02115, USA.
¹¹ Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
¹² Center for Immunology and Inflammatory Disease, Massachusetts General Hospital, Boston, MA 02115, USA.
¹³ Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁵ Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
¹⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: cwu@partners.org.

Abstract

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.

Keywords: CLL; Notch signaling; RNA sequencing; SF3B1; alternative splicing.

MeSH terms

Alternative Splicing*
Cell Line, Tumor
Dishevelled Proteins / genetics
Gene Expression Profiling / methods*
Gene Expression Regulation, Neoplastic
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
Mutation*
Phosphoproteins / genetics*
RNA Splicing Factors / genetics*
Receptors, Notch / genetics
Signal Transduction

Substances

DVL2 protein, human
Dishevelled Proteins
Phosphoproteins
RNA Splicing Factors
Receptors, Notch
SF3B1 protein, human

Abstract

MeSH terms

Substances

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