Departments of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Division of Stem Cell Therapy, Center for Stem Cell Biology and Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Leukemia. 2014 Sep;28(9):1844-50. doi: 10.1038/leu.2014.73. Epub 2014 Feb 18.
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.
SF3B1 是 mRNA 剪接机制的核心组成部分，在伴骨髓增生异常的髓系肿瘤中经常发生突变，尤其是那些以环形铁幼粒细胞增多为特征的肿瘤。RNA 剪接失调与 SF3B1 突变肿瘤的发病机制有关，但 SF3B1 突变与骨髓增生异常和环形铁幼粒细胞形成的具体机制尚不清楚。我们利用 Sf3b1 杂合缺失小鼠研究了 SF3B1 在正常造血中的功能作用。与 Sf3b1(+/+)小鼠相比，Sf3b1(+/-)小鼠的造血干细胞（CD34(-)cKit(+)ScaI(+)Lin(-)细胞或 CD34(-)KSL 细胞）数量明显减少，但 Sf3b1(+/-)小鼠的造血功能大体正常。当与 Sf3b1(+/+)骨髓细胞进行竞争移植时，Sf3b1(+/-)干细胞在致死性照射小鼠中的重建能力受损。Sf3b1(+/-)小鼠中环形铁幼粒细胞数量没有增加，也没有骨髓增生异常的证据。这些数据表明，SF3B1 在调节造血干细胞方面发挥重要作用，而 SF3B1 杂合不足本身与伴环形铁幼粒细胞的骨髓增生异常综合征表型无关。
