红系无效造血是骨髓增生异常综合征（MDS）-难治性贫血伴环状铁粒幼红细胞增多（RARS）主要病理特征。前期研究发现MDS-RARS患者存在剪接复合体基因SF3B1高频功能减退性突变，突变型患者红系无效造血更显著，但具体作用机制不明确。我们首次发现导致MDS-RARS红系无效造血重要基因Bcl-x可变剪接产物Bcl-xL在SF3B1突变患者中表达显著减低，提示SF3B1突变可能通过对Bcl-x异常可变剪接参与MDS-RARS红系无效造血。本课题拟在向红系分化的k562细胞系和正常人骨髓CD34+细胞、MDS-RARS原代细胞中多层面上研究：①SF3B1直接调控Bcl-x 可变剪接；②SF3B1低表达导致红系无效造血；③SF3B1通过Bcl-x异常剪接参与红系无效造血，以阐述SF3B1突变在MDS-RARS红系无效造血中作用机制,为MDS-RARS发病机制研究及治疗提供新途径。

Myelodysplastic syndromes(MDS)-refractory anemia with ring sideroblasts (RARS) is mainly characterized by ineffective erythropoiesis in erythroblasts. Our previous study had demonstrated the mutations in splicing factor 3b subunit 1 (SF3B1) were the most frequently identified genetic abnormalities in RARS and may act as a loss of function. Subjects with SF3B1 mutations often had more severely ineffective erythropoiesis compared to subjects without mutation. However, many questions remain unanswered in linking SF3B1 dysfunction to MDS biology like the downstream targets and the exact mechanisms contribute to RARS ineffective erythropoiesis. We found that RARS with SF3B1 mutations had reduced Bcl-xL expression, an alternative pre-mRNA splicing product of Bcl-x which actes as a main medicator of ineffective erythroiesis in RARS. So, we will use in induced erythroid differentiation system of k562, normal bone marrow CD34+ progenitors and RARS primary cell to identify ①whether SF3B1 can directly regulate Bcl-x alternative splicing② the effect of downregulation of SF3B1 on RARS ineffective erythropoiesis , and ③whether downregulation of SF3B1 regulate RARS ineffective erythropoiesis through Bcl-x alternative splicing. This project will provide new insights into the pathogenesis and treatment of MDS-RARS as expected, and has great significance for fully clarifying the role of SF3B1 in ineffective erythropoiesis.