Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia.
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.
Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
Lili
L
Wang
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.
Angela N
AN
Brooks
Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
Jean
J
Fan
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.
Youzhong
Y
Wan
Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA.
Rutendo
R
Gambe
Fluidigm Corporation, South San Francisco, CA 94080, USA.
Shuqiang
S
Li
Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA.
Sarah
S
Hergert
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Shanye
S
Yin
Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
Samuel S
SS
Freeman
Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
Joshua Z
JZ
Levin
Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
Lin
L
Fan
H3 Biomedicine, Cambridge, MA 02141, USA.
Michael
M
Seiler
H3 Biomedicine, Cambridge, MA 02141, USA.
Silvia
S
Buonamici
H3 Biomedicine, Cambridge, MA 02141, USA.
Peter G
PG
Smith
Harvard Medical School, Boston, MA 02115, USA.
Kevin F
KF
Chau
Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
Carrie L
CL
Cibulskis
Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA.
Wandi
W
Zhang
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Laura Z
LZ
Rassenti
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Emanuela M
EM
Ghia
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Thomas J
TJ
Kipps
Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA.
Stacey
S
Fernandes
Center for Immunology and Inflammatory Disease, Massachusetts General Hospital, Boston, MA 02115, USA.
Donald B
DB
Bloch
Harvard Medical School, Boston, MA 02115, USA.
Dylan
D
Kotliar
Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
Dan A
DA
Landau
Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA.
Sachet A
SA
Shukla
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Jon C
JC
Aster
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Robin
R
Reed
Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
David S
DS
DeLuca
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.
Jennifer R
JR
Brown
Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Donna
D
Neuberg
Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
Gad
G
Getz
Fluidigm Corporation, South San Francisco, CA 94080, USA.
Kenneth J
KJ
Livak
Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 540, 44 Binney Street, Boston, MA 02115, USA.
Matthew M
MM
Meyerson
Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
Peter V
PV
Kharchenko
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.
Catherine J
CJ
Wu
D017398:Alternative Splicing; D045744:Cell Line, Tumor; D000072261:Dishevelled Proteins / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics*; D000072260:RNA Splicing Factors / Q000235:genetics*; D051880:Receptors, Notch / Q000235:genetics; D015398:Signal Transduction
C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D051880:Receptors, Notch; C112491:SF3B1 protein, human
CLL; Notch signaling; RNA sequencing; SF3B1; alternative splicing