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

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. KippsStacey 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

Research output: Contribution to journal › Article › peer-review

149 Scopus citations

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.

Original language	English (US)
Pages (from-to)	750-763
Number of pages	14
Journal	Cancer Cell
Volume	30
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2016.10.005
State	Published - Nov 14 2016
Externally published	Yes

Keywords

CLL
Notch signaling
RNA sequencing
SF3B1
alternative splicing

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2016.10.005

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Wang, L., Brooks, A. N., Fan, J., Wan, Y., Gambe, R., Li, S., Hergert, S., Yin, S., Freeman, S. S., Levin, J. Z., Fan, L., Seiler, M., Buonamici, S., Smith, P. G., Chau, K. F., Cibulskis, C. L., Zhang, W., Rassenti, L. Z., Ghia, E. M., ... Wu, C. J. (2016). Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia. Cancer Cell, 30(5), 750-763. https://doi.org/10.1016/j.ccell.2016.10.005

Wang, 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 2016, 'Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia', Cancer Cell, vol. 30, no. 5, pp. 750-763. https://doi.org/10.1016/j.ccell.2016.10.005

@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 = "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",

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T1 - Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia

AU - Wang, Lili

AU - Brooks, Angela N.

AU - Fan, Jean

AU - Wan, Youzhong

AU - Gambe, Rutendo

AU - Li, Shuqiang

AU - Hergert, Sarah

AU - Yin, Shanye

AU - Freeman, Samuel S.

AU - Levin, Joshua Z.

AU - Fan, Lin

AU - Seiler, Michael

AU - Buonamici, Silvia

AU - Smith, Peter G.

AU - Chau, Kevin F.

AU - Cibulskis, Carrie L.

AU - Zhang, Wandi

AU - Rassenti, Laura Z.

AU - Ghia, Emanuela M.

AU - Kipps, Thomas J.

AU - Fernandes, Stacey

AU - Bloch, Donald B.

AU - Kotliar, Dylan

AU - Landau, Dan A.

AU - Shukla, Sachet A.

AU - Aster, Jon C.

AU - Reed, Robin

AU - DeLuca, David S.

AU - Brown, Jennifer R.

AU - Neuberg, Donna

AU - Getz, Gad

AU - Livak, Kenneth J.

AU - Meyerson, Matthew M.

AU - Kharchenko, Peter V.

AU - Wu, Catherine J.

PY - 2016/11/14

Y1 - 2016/11/14

N2 - 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.

AB - 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.

KW - CLL

KW - Notch signaling

KW - RNA sequencing

KW - SF3B1

KW - alternative splicing

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DO - 10.1016/j.ccell.2016.10.005

M3 - Article

C2 - 27818134

AN - SCOPUS:85006150322

SN - 1535-6108

VL - 30

SP - 750

EP - 763

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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