首页> 美国卫生研究院文献>Molecular and Cellular Biology >SRSF2 Is Essential for Hematopoiesis and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative Pre-mRNA Splicing
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SRSF2 Is Essential for Hematopoiesis and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative Pre-mRNA Splicing

机译:SRSF2是造血必不可少的其骨髓增生异常综合征相关的突变失调替代前mRNA剪接。

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摘要

Myelodysplastic syndromes (MDS) are a group of neoplasms characterized by ineffective myeloid hematopoiesis and various risks for leukemia. SRSF2, a member of the serine/arginine-rich (SR) family of splicing factors, is one of the mutation targets associated with poor survival in patients suffering from myelodysplastic syndromes. Here we report the biological function of SRSF2 in hematopoiesis by using conditional knockout mouse models. Ablation of SRSF2 in the hematopoietic lineage caused embryonic lethality, and Srsf2-deficient fetal liver cells showed significantly enhanced apoptosis and decreased levels of hematopoietic stem/progenitor cells. Induced ablation of SRSF2 in adult Mx1-Cre Srsf2flox/flox mice upon poly(I):poly(C) injection demonstrated a significant decrease in lineage Sca+ c-Kit+ cells in bone marrow. To reveal the functional impact of myelodysplastic syndromes-associated mutations in SRSF2, we analyzed splicing responses on the MSD-L cell line and found that the missense mutation of proline 95 to histidine (P95H) and a P95-to-R102 in-frame 8-amino-acid deletion caused significant changes in alternative splicing. The affected genes were enriched in cancer development and apoptosis. These findings suggest that intact SRSF2 is essential for the functional integrity of the hematopoietic system and that its mutations likely contribute to development of myelodysplastic syndromes.
机译:骨髓增生异常综合症(MDS)是一组以骨髓血细胞生成无效和白血病风险为特征的肿瘤。 SRSF2是富含丝氨酸/精氨酸(SR)的剪接因子家族的成员,是与患有骨髓增生异常综合症的患者存活率低相关的突变靶标之一。在这里,我们通过使用条件基因敲除小鼠模型报告SRSF2在造血中的生物学功能。造血谱系中SRSF2的切除引起胚胎致死性,Srsf2缺陷型胎儿肝细胞显示出明显的凋亡增强和造血干/祖细胞水平降低。 poly(I):poly(C)注射后成年Mx1-Cre Srsf2 flox / flox 小鼠中SRSF2的诱导消融表明血统- Sca 显着降低骨髓中的+ c-Kit + 细胞。为了揭示SRSF2中与骨髓增生异常综合征相关的突变的功能影响,我们分析了MSD-L细胞系上的剪接反应,发现脯氨酸95对组氨酸(P95H)和P95至R102的错义突变符合读框8 -氨基酸缺失导致替代剪接的显着变化。受影响的基因丰富了癌症的发展和凋​​亡。这些发现表明,完整的SRSF2对于造血系统的功能完整性至关重要,并且其突变可能有助于骨髓增生异常综合症的发展。

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