title: SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition.
abstract: Mutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2's normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2, which triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in the splicing of key regulators, and impaired hematopoiesis.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.affiliation: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Janine O
authors.initials: JO
authors.lastname: Ilagan
authors.affiliation: Hematology, Yale Comprehensive Cancer Center and Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Institute for Molecular Biology and Biophysics, ETH, 8093 Zürich, Switzerland.
authors.forename: Gerrit M
authors.initials: GM
authors.lastname: Daubner
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Stanley C-W
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Division of Medical Oncology, School of Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: Aravind
authors.initials: A
authors.lastname: Ramakrishnan
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Young Rock
authors.initials: YR
authors.lastname: Chung
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Micol
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Michele E
authors.initials: ME
authors.lastname: Murphy
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Hana
authors.initials: H
authors.lastname: Cho
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Ahmad S
authors.initials: AS
authors.lastname: Zebari
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Shlomzion
authors.initials: S
authors.lastname: Aumann
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Park
authors.affiliation: H3 Biomedicine, Cambridge, MA 03129, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Buonamici
authors.affiliation: H3 Biomedicine, Cambridge, MA 03129, USA.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Smith
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Division of Medical Oncology, School of Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: H Joachim
authors.initials: HJ
authors.lastname: Deeg
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM) U1009, Institut Gustave Roussy, 94805 Villejuif, France; Université Paris-Sud, 91400 Orsay, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Lobry
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
authors.forename: Yorgo
authors.initials: Y
authors.lastname: Modis
authors.affiliation: Institute for Molecular Biology and Biophysics, ETH, 8093 Zürich, Switzerland.
authors.forename: Frederic H-T
authors.initials: FH
authors.lastname: Allain
authors.affiliation: Hematology, Yale Comprehensive Cancer Center and Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Halene
authors.affiliation: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address: rbradley@fhcrc.org.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Bradley
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: abdelwao@mskcc.org.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
mesh_terms: D000818:Animals; D000071221:Enhancer of Zeste Homolog 2 Protein; D005091:Exons; D015870:Gene Expression; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D012326:RNA Splicing; D012261:Ribonucleoproteins / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors
chemical_list: D009687:Nuclear Proteins; D012261:Ribonucleoproteins; C499372:SRSF2 protein, mouse; D000068103:Serine-Arginine Splicing Factors; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2