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Mol Cell Biol. 2015 Sep 1;35(17):3071-82. doi: 10.1128/MCB.00202-15. Epub 2015 Jun 29.

SRSF2 Is Essential for Hematopoiesis, and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative Pre-mRNA Splicing.

Author information

1
Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
2
Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
3
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
4
Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA xdfu@ucsd.edu dez@ucsd.edu.
5
Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA Department of Pathology, University of California, San Diego, La Jolla, California, USA xdfu@ucsd.edu dez@ucsd.edu.

Abstract

Myelodysplastic syndromes (MDS) are a group of neoplasms characterized by ineffective myeloid hematopoiesis and various risks for leukemia. SRSF2, a member of the serine/arginine-rich (SR) family of splicing factors, is one of the mutation targets associated with poor survival in patients suffering from myelodysplastic syndromes. Here we report the biological function of SRSF2 in hematopoiesis by using conditional knockout mouse models. Ablation of SRSF2 in the hematopoietic lineage caused embryonic lethality, and Srsf2-deficient fetal liver cells showed significantly enhanced apoptosis and decreased levels of hematopoietic stem/progenitor cells. Induced ablation of SRSF2 in adult Mx1-Cre Srsf2(flox/flox) mice upon poly(I):poly(C) injection demonstrated a significant decrease in lineage(-) Sca(+) c-Kit(+) cells in bone marrow. To reveal the functional impact of myelodysplastic syndromes-associated mutations in SRSF2, we analyzed splicing responses on the MSD-L cell line and found that the missense mutation of proline 95 to histidine (P95H) and a P95-to-R102 in-frame 8-amino-acid deletion caused significant changes in alternative splicing. The affected genes were enriched in cancer development and apoptosis. These findings suggest that intact SRSF2 is essential for the functional integrity of the hematopoietic system and that its mutations likely contribute to development of myelodysplastic syndromes.

PMID:
26124281
PMCID:
PMC4525309
DOI:
10.1128/MCB.00202-15
[Indexed for MEDLINE]
Free PMC Article

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