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

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

Author information

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
  • 2Department 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.
  • 3Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
  • 4Department 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.
  • 5Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA.
  • 6Fluidigm Corporation, South San Francisco, CA 94080, USA.
  • 7Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 8Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
  • 9H3 Biomedicine, Cambridge, MA 02141, USA.
  • 10Harvard Medical School, Boston, MA 02115, USA.
  • 11Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • 12Center for Immunology and Inflammatory Disease, Massachusetts General Hospital, Boston, MA 02115, USA.
  • 13Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 14Department 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.
  • 15Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 16Department 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

PMID:
27818134
PMCID:
PMC5127278
[Available on 2017-11-14]
DOI:
10.1016/j.ccell.2016.10.005
[PubMed - in process]
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