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Blood. 2018 Feb 8;131(6):621-635. doi: 10.1182/blood-2017-01-762393. Epub 2017 Nov 16.

Physiological Srsf2 P95H expression causes impaired hematopoietic stem cell functions and aberrant RNA splicing in mice.

Author information

1
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
2
Division of Stem Cell Therapy, Center for Stem Cell Biology and Medicine and.
3
Department of Pathology, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
4
Clinical Research Center, National Hospital Organization, Nagoya Medical Center, Nagoya, Japan.
5
Chromosome Engineering Team, Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Japan.
6
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; and.
7
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA.

Abstract

Splicing factor mutations are characteristic of myelodysplastic syndromes (MDS) and related myeloid neoplasms and implicated in their pathogenesis, but their roles in the development of MDS have not been fully elucidated. In the present study, we investigated the consequence of mutant Srsf2 expression using newly generated Vav1-Cre-mediated conditional knockin mice. Mice carrying a heterozygous Srsf2 P95H mutation showed significantly reduced numbers of hematopoietic stem and progenitor cells (HSPCs) and differentiation defects both in the steady-state condition and transplantation settings. Srsf2-mutated hematopoietic stem cells (HSCs) showed impaired long-term reconstitution compared with control mice in competitive repopulation assays. Although the Srsf2 mutant mice did not develop MDS under the steady-state condition, when their stem cells were transplanted into lethally irradiated mice, the recipients developed anemia, leukopenia, and erythroid dysplasia, which suggests the role of replicative stress in the development of an MDS-like phenotype in Srsf2-mutated mice. RNA sequencing of the Srsf2-mutated HSPCs revealed a number of abnormal splicing events and differentially expressed genes, including several potential targets implicated in the pathogenesis of hematopoietic malignancies, such as Csf3r, Fyn, Gnas, Nsd1, Hnrnpa2b1, and Trp53bp1 Among the mutant Srsf2-associated splicing events, most commonly observed were the enhanced inclusion and/or exclusion of cassette exons, which were caused by the altered consensus motifs for the recognition of exonic splicing enhancers. Our findings suggest that the mutant Srsf2 leads to a compromised HSC function by causing abnormal RNA splicing and expression, contributing to the deregulated hematopoiesis that recapitulates the MDS phenotypes, possibly as a result of additional genetic and/or environmental insults.

PMID:
29146882
PMCID:
PMC5888285
DOI:
10.1182/blood-2017-01-762393
[Indexed for MEDLINE]
Free PMC Article

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