TY - JOUR
T1 - Physiological Srsf2 P95H expression causes impaired hematopoietic stem cell functions and aberrant RNA splicing in mice
AU - Kon, Ayana
AU - Yamazaki, Satoshi
AU - Nannya, Yasuhito
AU - Kataoka, Keisuke
AU - Ota, Yasunori
AU - Nakagawa, Masahiro Marshall
AU - Yoshida, Kenichi
AU - Shiozawa, Yusuke
AU - Morita, Maiko
AU - Yoshizato, Tetsuichi
AU - Sanada, Masashi
AU - Nakayama, Manabu
AU - Koseki, Haruhiko
AU - Nakauchi, Hiromitsu
AU - Ogawa, Seishi
N1 - Funding Information:
This work was supported by a Grant-in-Aid for Scientific Research (MEXT/ JSPS KAKENHI JP26221308 and JP26253060 to S.O., JP16K19574 and JP14J03784 to A.K., and JP26115009 to M.S.); a Grant-in-Aid from the Japan Agency for Medical Research and Development (Project for Development of Innovative Research on Cancer Therapeutics [16cm0106501h0001 to S.O.], Practical Research for Innovative Cancer Control Project [15ck0106073h0002 and 16ck0106073h0003 to S.O.], and Strategic International Collaborative Research Program [16jm0210034h0104 to H.N.]); and grants from the Takeda Science Foundation (S.O.) and the Uehara Memorial Foundation (A.K.).
PY - 2018/2/8
Y1 - 2018/2/8
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2017-01-762393
DO - 10.1182/blood-2017-01-762393
M3 - Article
C2 - 29146882
AN - SCOPUS:85041891659
VL - 131
SP - 621
EP - 635
JO - Blood
JF - Blood
SN - 0006-4971
IS - 6
ER -