Blood Cancer UK Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, And NIHR Oxford BRC Haematology Theme, Oxford, UK.
Adv Biol Regul. 2021 Jan;79:100776. doi: 10.1016/j.jbior.2020.100776. Epub 2020 Dec 25.
The myelodysplastic syndromes (MDS) are common myeloid malignancies. Mutations in genes encoding different components of the spliceosome occur in more than half of all MDS patients. SF3B1 is the most frequently mutated splicing factor gene in MDS, and there is a strong association between SF3B1 mutations and the presence of ring sideroblasts in the bone marrow of MDS patients. It has been recently proposed that SF3B1 mutant MDS should be recognized as a distinct nosologic entity. Splicing factor mutations cause aberrant pre-mRNA splicing of many target genes, some of which have been shown to impact on hematopoiesis in functional studies. Emerging data show that some of the downstream effects of different mutated splicing factors converge on common cellular processes, such as hyperactivation of NF-κB signaling and increased R-loops. The aberrantly spliced target genes and the dysregulated pathways and cellular processes associated with splicing factor mutations provided the rationale for new potential therapeutic approaches to target MDS cells with mutations of SF3B1 and other splicing factors.
骨髓增生异常综合征（MDS）是常见的髓系恶性肿瘤。超过一半的 MDS 患者存在剪接体不同成分编码基因的突变。SF3B1 是 MDS 中突变频率最高的剪接因子基因，SF3B1 突变与 MDS 患者骨髓中环状铁幼粒细胞的存在之间存在很强的关联。最近有人提出，SF3B1 突变 MDS 应被视为一种独特的分类实体。剪接因子突变导致许多靶基因的前体 mRNA 剪接异常，其中一些靶基因在功能研究中已被证明会影响造血。新出现的数据表明，不同突变剪接因子的一些下游效应会集中在共同的细胞过程上，例如 NF-κB 信号的过度激活和 R 环的增加。与剪接因子突变相关的异常剪接靶基因和失调的途径和细胞过程为针对 SF3B1 和其他剪接因子突变的 MDS 细胞的新的潜在治疗方法提供了依据。
