Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations
Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations
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DOI：
10.1182/blood-2018-04-843771
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发表时间：
2018-09-20
期刊：
影响因子：
20.3
通讯作者：
Boultwood, Jacqueline
中科院分区：
文献类型：
--
作者：
Pellagatti, Andrea;Armstrong, Richard N.;Boultwood, Jacqueline
SF 3B 1、SRSF 2和U2 AF 1是骨髓增生异常综合征（MDS）中最常见的突变剪接因子基因。我们已经进行了全面和系统的分析，以确定这些常见的突变剪接因子对骨髓干/祖细胞和剪接因子突变型MDS中的红系和髓系前体细胞中的前mRNA剪接的影响。使用RNA-seq，我们确定了84例MDS患者CD 34（+）细胞中异常剪接的基因和失调的通路。剪接因子突变导致剪接的不同改变，并在很大程度上影响不同的基因，但这些基因在共同的失调途径和细胞过程中会聚，集中在RNA剪接，蛋白质合成和线粒体功能障碍，这表明MDS中的共同作用机制。许多这些失调的途径和细胞过程可以链接到已知的疾病病理生理学与剪接因子突变在MDS中，而其他几个以前没有与MDS，如沉默调节蛋白信号。我们确定了与临床变量相关的异常剪接事件，以及独立预测MDS生存率的亚型，并将粘着斑和细胞外外来体调节异常作为生存率差的驱动因素。在剪接因子突变型MDS的MDS受影响谱系中鉴定了异常剪接基因和失调途径。功能研究表明，有丝分裂调节因子SEPT 2和AKAP 8（分别为SF 3B 1和SRSF 2突变的异常剪接靶基因）的敲低导致红系细胞生长和分化受损。这项研究阐明了常见剪接体突变对MDS表型的影响，并为疾病病理生理学提供了新的见解。
SF3B1, SRSF2, and U2AF1 are the most frequently mutated splicing factor genes in the myelodysplastic syndromes (MDS). We have performed a comprehensive and systematic analysis to determine the effect of these commonly mutated splicing factors on pre-mRNA splicing in the bone marrow stem/progenitor cells and in the erythroid and myeloid precursors in splicing factor mutant MDS. Using RNA-seq, we determined the aberrantly spliced genes and dysregulated pathways in CD34(+) cells of 84 patients with MDS. Splicing factor mutations result in different alterations in splicing and largely affect different genes, but these converge in common dysregulated pathways and cellular processes, focused on RNA splicing, protein synthesis, and mitochondrial dysfunction, suggesting common mechanisms of action in MDS. Many of these dysregulated pathways and cellular processes can be linked to the known disease pathophysiology associated with splicing factor mutations in MDS, whereas several others have not been previously associated with MDS, such as sirtuin signaling. We identified aberrantly spliced events associated with clinical variables, and isoforms that independently predict survival in MDS and implicate dysregulation of focal adhesion and extracellular exosomes as drivers of poor survival. Aberrantly spliced genes and dysregulated pathways were identified in the MDS-affected lineages in splicing factor mutant MDS. Functional studies demonstrated that knockdown of the mitosis regulators SEPT2 and AKAP8, aberrantly spliced target genes of SF3B1 and SRSF2 mutations, respectively, led to impaired erythroid cell growth and differentiation. This study illuminates the effect of the common spliceosome mutations on the MDS phenotype and provides novel insights into disease pathophysiology.