@article{07c682e8c24344308b8aa1f643cd5804,
title = "Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia",
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",
author = "Lili Wang and Brooks, {Angela N.} and Jean Fan and Youzhong Wan and Rutendo Gambe and Shuqiang Li and Sarah Hergert and Shanye Yin and Freeman, {Samuel S.} and Levin, {Joshua Z.} and Lin Fan and Michael Seiler and Silvia Buonamici and Smith, {Peter G.} and Chau, {Kevin F.} and Cibulskis, {Carrie L.} and Wandi Zhang and Rassenti, {Laura Z.} and Ghia, {Emanuela M.} and Kipps, {Thomas J.} and Stacey Fernandes and Bloch, {Donald B.} and Dylan Kotliar and Landau, {Dan A.} and Shukla, {Sachet A.} and Aster, {Jon C.} and Robin Reed and DeLuca, {David S.} and Brown, {Jennifer R.} and Donna Neuberg and Gad Getz and Livak, {Kenneth J.} and Meyerson, {Matthew M.} and Kharchenko, {Peter V.} and Wu, {Catherine J.}",
note = "Funding Information: The authors thank A. D'Andrea, G. Gould, and C. Burge for critical discussions, and J. Wong, G. Harris, and B.Z. Tong for excellent technical support. We thank J. Daley, S. Lazo-Kallanian, K. Cowens, and S. Paula of the DFCI Flow Cytometry facility for their assistance in single-cell sorting. We further thank M. Imielinksi, S. Lee, and K. Slowikowski for assistance with sequence analysis. This work was in part supported by funding from the NIH to the CLL Research Consortium (PO1-CA81534). L.W. was supported by the Lymphoma Research Foundation (LRF) postdoctoral fellowship. A.N.B. was a Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG-2138-12). J.F. was supported by the National Science Foundation Graduate Research Fellowship (DGE1144152). Y.W. was supported by a fellowship from the Leukemia and Lymphoma Society (LLS). C.J.W. acknowledges support from the Blavatnik Family Foundation, the LRF, NHLBI (1R01HL103532-01; 1R01HL116452-01) and NCI (1R01CA155010-01A1; 1U10CA180861-01), and is a recipient of an LLS Translational Research Program and Scholar Award and of an AACR SU2C Innovative Research Grant. M.S., S.B., and P.G.S. are employees and shareholders of H3 Biomedicine. C.J.W. is co-founder and scientific advisory board member of Neon Therapeutics, Inc. Funding Information: The authors thank A. D'Andrea, G. Gould, and C. Burge for critical discussions, and J. Wong, G. Harris, and B.Z. Tong for excellent technical support. We thank J. Daley, S. Lazo-Kallanian, K. Cowens, and S. Paula of the DFCI Flow Cytometry facility for their assistance in single-cell sorting. We further thank M. Imielinksi, S. Lee, and K. Slowikowski for assistance with sequence analysis. This work was in part supported by funding from the NIH to the CLL Research Consortium ( PO1-CA81534 ). L.W. was supported by the Lymphoma Research Foundation (LRF) postdoctoral fellowship. A.N.B. was a Merck Fellow of the Damon Runyon Cancer Research Foundation ( DRG-2138-12 ). J.F. was supported by the National Science Foundation Graduate Research Fellowship ( DGE1144152 ). Y.W. was supported by a fellowship from the Leukemia and Lymphoma Society (LLS). C.J.W. acknowledges support from the Blavatnik Family Foundation , the LRF, NHLBI ( 1R01HL103532-01 ; 1R01HL116452-01 ) and NCI ( 1R01CA155010-01A1 ; 1U10CA180861-01 ), and is a recipient of an LLS Translational Research Program and Scholar Award and of an AACR SU2C Innovative Research Grant. M.S., S.B., and P.G.S. are employees and shareholders of H3 Biomedicine. C.J.W. is co-founder and scientific advisory board member of Neon Therapeutics, Inc. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = nov,
day = "14",
doi = "10.1016/j.ccell.2016.10.005",
language = "English (US)",
volume = "30",
pages = "750--763",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "5",
}
