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Stem Cells

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 (CD34cKit+ScaI+Lin cells or CD34KSL 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.

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Acknowledgements

We thank Y Yamazaki for his excellent technical support on flow cytometric analyses and cell sorting. This work was supported in part of Grants-in-aid for Scientific Research (nos. 24390242 and 23249052) and Grant-in-Aid for Scientific Research on Innovative Areas (no. 4201), MEXT, Japan, and grants from the Princes Takamatsu Cancer Research Fund and the Japan Leukemia Research Fund.

Author Contributions

MM, RY, MS, MO and HN performed mouse experiments; MM, AS-O, Y Shiozawa, KY, Y Shiraishi and SM performed bioinformatics analyses of RNA sequencing data; KI and HK generated Sf3b1 knockout mice; MM, RY, MS and AS-O analyzed the data and generated figures and table; and MM, MS and SO designed the experiments and wrote the manuscript. All authors participated in the discussion and interpretation of data and results.

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Correspondence to S Ogawa.

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Matsunawa, M., Yamamoto, R., Sanada, M. et al. Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia. Leukemia 28, 1844–1850 (2014). https://doi.org/10.1038/leu.2014.73

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