title: SRSF2 Is Essential for Hematopoiesis, and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative Pre-mRNA Splicing.
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.
authors.affiliation: Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Komeno
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Yi-Jou
authors.initials: YJ
authors.lastname: Huang
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Leo
authors.initials: L
authors.lastname: Lin
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: YiJun
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Dora D
authors.initials: DD
authors.lastname: Monterroza
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Hairi
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Russell C
authors.initials: RC
authors.lastname: DeKelver
authors.affiliation: Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001773:Blood Cells / Q000166:cytology*; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D057809:HEK293 Cells; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D008099:Liver / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011070:Poly I-C / Q000494:pharmacology; D034622:RNA Interference; D012322:RNA Precursors / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors
chemical_list: D009687:Nuclear Proteins; D012322:RNA Precursors; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins; C499372:SRSF2 protein, mouse; D000068103:Serine-Arginine Splicing Factors; D011070:Poly I-C