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Cancer Cell DOI:10.1016/j.ccell.2016.10.005

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

Publication TypeJournal Article
Year of Publication2016
AuthorsWang, L, Brooks, AN, Fan, J, Wan, Y, Gambe, R, Li, S, Hergert, S, Yin, S, Freeman, SS, Levin, JZ, Fan, L, Seiler, M, Buonamici, S, Smith, PG, Chau, KF, Cibulskis, CL, Zhang, W, Rassenti, LZ, Ghia, EM, Kipps, TJ, Fernandes, S, Bloch, DB, Kotliar, D, Landau, DA, Shukla, SA, Aster, JC, Reed, R, DeLuca, DS, Brown, JR, Neuberg, D, Getz, G, Livak, KJ, Meyerson, MM, Kharchenko, PV, Wu, CJ
JournalCancer Cell
Volume30
Issue5
Pages750-763
Date Published2016 Nov 14
ISSN1878-3686
KeywordsAlternative Splicing, Cell Line, Tumor, Dishevelled Proteins, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mutation, Phosphoproteins, Receptors, Notch, RNA Splicing Factors, Signal Transduction
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.

DOI10.1016/j.ccell.2016.10.005
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/27818134?dopt=Abstract

Alternate JournalCancer Cell
PubMed ID27818134
PubMed Central IDPMC5127278
Grant ListU10 CA180861 / CA / NCI NIH HHS / United States
R01 CA182461 / CA / NCI NIH HHS / United States
F31 CA206236 / CA / NCI NIH HHS / United States
R01 HL131768 / HL / NHLBI NIH HHS / United States
R01 HL103532 / HL / NHLBI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
R50 CA211482 / CA / NCI NIH HHS / United States
P01 CA206978 / CA / NCI NIH HHS / United States
P01 CA081534 / CA / NCI NIH HHS / United States
R01 CA184922 / CA / NCI NIH HHS / United States
R01 CA155010 / CA / NCI NIH HHS / United States
R01 GM043375 / GM / NIGMS NIH HHS / United States
R01 HL116452 / HL / NHLBI NIH HHS / United States