title: Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia.
abstract: SF3B1 is a core component of the mRNA splicing machinery and frequently mutated in myeloid neoplasms with myelodysplasia, particularly in those characterized by the presence of increased ring sideroblasts. Deregulated RNA splicing is implicated in the pathogenesis of SF3B1-mutated neoplasms, but the exact mechanism by which the SF3B1 mutation is associated with myelodysplasia and the increased ring sideroblasts formation is still unknown. We investigated the functional role of SF3B1 in normal hematopoiesis utilizing Sf3b1 heterozygous-deficient mice. Sf3b1(+/-) mice had a significantly reduced number of hematopoietic stem cells (CD34(-)cKit(+)ScaI(+)Lin(-) cells or CD34(-)KSL cells) compared with Sf3b1(+/+) mice, but hematopoiesis was grossly normal in Sf3b1(+/-) mice. When transplanted competitively with Sf3b1(+/+) bone marrow cells, Sf3b1(+/-) stem cells showed compromised reconstitution capacity in lethally irradiated mice. There was no increase in the number of ring sideroblasts or evidence of myeloid dysplasia in Sf3b1(+/-) mice. These data suggest that SF3B1 plays an important role in the regulation of hematopoietic stem cells, whereas SF3B1 haploinsufficiency itself is not associated with the myelodysplastic syndrome phenotype with ring sideroblasts.
authors.affiliation: Departments of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Matsunawa
authors.affiliation: Division of Stem Cell Therapy, Center for Stem Cell Biology and Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Yamamoto
authors.affiliation: Departments of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Departments of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Sato-Otsubo
authors.affiliation: Departments of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shiozawa
authors.affiliation: Departments of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Division of Stem Cell Therapy, Center for Stem Cell Biology and Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Otsu
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: 1] Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan [2] Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Research Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Isono
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Research Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Division of Stem Cell Therapy, Center for Stem Cell Biology and Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nakauchi
authors.affiliation: Departments of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D057895:Haploinsufficiency; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*
chemical_list: D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C491799:Sf3b1 protein, mouse