SRSF2 Is Essential for Hematopoiesis, and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative Pre-mRNA Splicing
SRSF2 Is Essential for Hematopoiesis, and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative Pre-mRNA Splicing
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DOI：
10.1128/mcb.00202-15
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发表时间：
2015-09-01
影响因子：
5.3
通讯作者：
Zhang, Dong-Er
中科院分区：
文献类型：
--
作者：
Komeno, Yukiko;Huang, Yi-Jou;Zhang, Dong-Er
骨髓增生异常综合征（MDS）是一组以无效髓系造血和不同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，是骨髓增生异常综合征患者中与不良生存相关的突变靶点之一。在此，我们利用条件性基因敲除小鼠模型报告了SRSF2在造血过程中的生物学功能。在造血谱系中敲除SRSF2会导致胚胎致死，并且Srsf2缺陷的胎肝细胞显示出细胞凋亡显著增强以及造血干/祖细胞水平降低。在成年Mx1 - Cre Srsf2（flox/flox）小鼠中，注射聚肌苷酸 - 聚胞苷酸（poly(I): poly(C)）诱导敲除SRSF2后，骨髓中谱系（ - ）Sca（ + ）c - Kit（ + ）细胞显著减少。为了揭示骨髓增生异常综合征相关的SRSF2突变的功能影响，我们分析了MSD - L细胞系中的剪接反应，发现脯氨酸95突变为组氨酸（P95H）以及P95到R102的8个氨基酸的框内缺失导致可变剪接发生显著变化。受影响的基因在癌症发展和细胞凋亡过程中富集。这些发现表明，完整的SRSF2对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征的发展。
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 Srsf2(flox/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.