Splicing factor mutations are characteristic of myelodysplastic syndromes (MDS) and related myeloid neoplasms and implicated in their pathogenesis, but their roles in the development of MDS have not been fully elucidated. In the present study, we investigated the consequence of mutant Srsf2 expression using newly generated Vav1-Cre-mediated conditional knockin mice. Mice carrying a heterozygous Srsf2 P95H mutation showed significantly reduced numbers of hematopoietic stem and progenitor cells (HSPCs) and differentiation defects both in the steady-state condition and transplantation settings. Srsf2-mutated hematopoietic stem cells (HSCs) showed impaired long-term reconstitution compared with control mice in competitive repopulation assays. Although the Srsf2 mutant mice did not develop MDS under the steady-state condition, when their stem cells were transplanted into lethally irradiated mice, the recipients developed anemia, leukopenia, and erythroid dysplasia, which suggests the role of replicative stress in the development of an MDS-like phenotype in Srsf2-mutated mice. RNA sequencing of the Srsf2-mutated HSPCs revealed a number of abnormal splicing events and differentially expressed genes, including several potential targets implicated in the pathogenesis of hematopoietic malignancies, such as Csf3r, Fyn, Gnas, Nsd1, Hnrnpa2b1, and Trp53bp1 Among the mutant Srsf2-associated splicing events, most commonly observed were the enhanced inclusion and/or exclusion of cassette exons, which were caused by the altered consensus motifs for the recognition of exonic splicing enhancers. Our findings suggest that the mutant Srsf2 leads to a compromised HSC function by causing abnormal RNA splicing and expression, contributing to the deregulated hematopoiesis that recapitulates the MDS phenotypes, possibly as a result of additional genetic and/or environmental insults.

中文翻译：

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生理学Srsf2P95H表达导致小鼠造血干细胞功能受损和RNA剪接异常

剪接因子突变是骨髓增生异常综合征 (MDS) 和相关髓系肿瘤的特征，并与它们的发病机制有关，但它们在 MDS 发展中的作用尚未完全阐明。在本研究中，我们使用新生成的 Vav1-Cre 介导的条件敲入小鼠研究了突变 Srsf2 表达的后果。携带杂合 Srsf2 P95H 突变的小鼠在稳态条件和移植环境中均表现出显着减少的造血干细胞和祖细胞 (HSPC) 和分化缺陷。在竞争性再增殖试验中，与对照小鼠相比，Srsf2 突变的造血干细胞 (HSC) 显示出长期重建受损。虽然 Srsf2 突变小鼠在稳态条件下没有发生 MDS，当他们的干细胞被移植到接受过致命辐射的小鼠中时，接受者出现了贫血、白细胞减少症和红细胞发育不良，这表明复制应激在 Srsf2 突变小鼠中 MDS 样表型发展中的作用。Srsf2 突变的 HSPCs 的 RNA 测序揭示了许多异常剪接事件和差异表达的基因，包括几个与造血系统恶性肿瘤发病机制有关的潜在靶点，如 Csf3r、Fyn、Gnas、Nsd1、Hnrnpa2b1 和 Trp53bp1 在突变体 Srsf2 中相关的剪接事件，最常见的是盒式外显子的增强包含和/或排除，这是由用于识别外显子剪接增强子的改变的共有基序引起的。