title: Depletion of Sf3b1 impairs proliferative capacity of hematopoietic stem cells but is not sufficient to induce myelodysplasia.
abstract: Numerous studies have recently reported mutations involving multiple components of the messenger RNA (mRNA) splicing machinery in patients with myelodysplastic syndrome (MDS). SF3B1 is mutated in 70% to 85% of refractory anemia with ringed sideroblasts (RARS) patients and is highly associated with the presence of RARS, although the pathological role of SF3B1 mutations in MDS-RARS has not been elucidated yet. Here, we analyzed the function of pre-mRNA splicing factor Sf3b1 in hematopoiesis. Sf3b1(+/-) mice maintained almost normal hematopoiesis and did not develop hematological malignancies during a long observation period. However, Sf3b1(+/-) cells had a significantly impaired capacity to reconstitute hematopoiesis in a competitive setting and exhibited some enhancement of apoptosis, but they did not show any obvious defects in differentiation. Additional depletion of Sf3b1 with shRNA in Sf3b1(+/-) hematopoietic stem cells (HSCs) severely compromised their proliferative capacity both in vitro and in vivo. Finally, we unexpectedly found no changes in the frequencies of sideroblasts in either Sf3b1(+/-) erythroblasts or cultured Sf3b1(+/-) erythroblasts expressing shRNA against Sf3b1. Our findings indicate that the level of Sf3b1 expression is critical for the proliferative capacity of HSCs, but the haploinsufficiency for Sf3b1 is not sufficient to induce a RARS-like phenotype.
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; Japan Science and Technology Corporation, Core Research for Evolutional Science and Technology, Gobancho, Chiyoda-ku, Tokyo, Japan;
authors.forename: Changshan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; Japan Science and Technology Corporation, Core Research for Evolutional Science and Technology, Gobancho, Chiyoda-ku, Tokyo, Japan;
authors.forename: Goro
authors.initials: G
authors.lastname: Sashida
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; Japan Science and Technology Corporation, Core Research for Evolutional Science and Technology, Gobancho, Chiyoda-ku, Tokyo, Japan;
authors.forename: Atsunori
authors.initials: A
authors.lastname: Saraya
authors.affiliation: Chromosome Unit, Central Laboratory, Tokyo Medical University, Tokyo, Japan; and.
authors.forename: Reiko
authors.initials: R
authors.lastname: Ishiga
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; Japan Science and Technology Corporation, Core Research for Evolutional Science and Technology, Gobancho, Chiyoda-ku, Tokyo, Japan;
authors.forename: Shuhei
authors.initials: S
authors.lastname: Koide
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; Japan Science and Technology Corporation, Core Research for Evolutional Science and Technology, Gobancho, Chiyoda-ku, Tokyo, Japan;
authors.forename: Motohiko
authors.initials: M
authors.lastname: Oshima
authors.affiliation: Laboratory for Developmental, RIKEN Research Center for Integrative Medical Sciences, RCAI-IMS, Yokohama, Japan.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Isono
authors.affiliation: Laboratory for Developmental, RIKEN Research Center for Integrative Medical Sciences, RCAI-IMS, Yokohama, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; Japan Science and Technology Corporation, Core Research for Evolutional Science and Technology, Gobancho, Chiyoda-ku, Tokyo, Japan;
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
mesh_terms: D000753:Anemia, Refractory / Q000235:genetics / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006238:Haploidy; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology*; D010750:Phosphoproteins / Q000235:genetics*; D012322:RNA Precursors / Q000235:genetics; D012326:RNA Splicing; D000072260:RNA Splicing Factors; D034741:RNA, Small Interfering / Q000235:genetics; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*
chemical_list: D010750:Phosphoproteins; D012322:RNA Precursors; D000072260:RNA Splicing Factors; D034741:RNA, Small Interfering; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human