Format

Send to

Choose Destination
Cancer Cell. 2015 May 11;27(5):617-30. doi: 10.1016/j.ccell.2015.04.006.

SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
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.
3
Hematology, Yale Comprehensive Cancer Center and Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
4
Institute for Molecular Biology and Biophysics, ETH, 8093 Zürich, Switzerland.
5
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.
6
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
7
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
8
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.
9
H3 Biomedicine, Cambridge, MA 03129, USA.
10
Institut National de la Santé et de la Recherche Medicale (INSERM) U1009, Institut Gustave Roussy, 94805 Villejuif, France; Université Paris-Sud, 91400 Orsay, France.
11
Howard Hughes Medical Institute and Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
12
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.
13
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.
14
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.

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.

Comment in

PMID:
25965569
PMCID:
PMC4429920
DOI:
10.1016/j.ccell.2015.04.006
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center