剪接因子突变在骨髓增生异常综合征:关键异常剪接基因在疾病病理生理和治疗中的作用

Q1 Biochemistry, Genetics and Molecular Biology
Andrea Pellagatti, Jacqueline Boultwood
{"title":"剪接因子突变在骨髓增生异常综合征:关键异常剪接基因在疾病病理生理和治疗中的作用","authors":"Andrea Pellagatti,&nbsp;Jacqueline Boultwood","doi":"10.1016/j.jbior.2022.100920","DOIUrl":null,"url":null,"abstract":"<div><p>Mutations of splicing factor genes (including <em>SF3B1</em>, <em>SRSF2</em>, <em>U2AF1</em> and <em>ZRSR2</em>) occur in more than half of all patients with myelodysplastic syndromes (MDS), a heterogeneous group of myeloid neoplasms. Splicing factor mutations lead to aberrant pre-mRNA splicing of many genes, some of which have been shown in functional studies to impact on hematopoiesis and to contribute to the MDS phenotype. This clearly demonstrates that impaired spliceosome function plays an important role in MDS pathophysiology. Recent studies that harnessed the power of induced pluripotent stem cell (iPSC) and CRISPR/Cas9 gene editing technologies to generate new iPSC-based models of splicing factor mutant MDS, have further illuminated the role of key downstream target genes. The aberrantly spliced genes and the dysregulated pathways associated with splicing factor mutations in MDS represent potential new therapeutic targets. Emerging data has shown that <em>IRAK4</em> is aberrantly spliced in <em>SF3B1</em> and <em>U2AF1</em> mutant MDS, leading to hyperactivation of NF-κB signaling. Pharmacological inhibition of IRAK4 has shown efficacy in pre-clinical studies and in MDS clinical trials, with higher response rates in patients with splicing factor mutations. Our increasing knowledge of the effects of splicing factor mutations in MDS is leading to the development of new treatments that may benefit patients harboring these mutations.</p></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"87 ","pages":"Article 100920"},"PeriodicalIF":0.0000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"4","resultStr":"{\"title\":\"Splicing factor mutations in the myelodysplastic syndromes: Role of key aberrantly spliced genes in disease pathophysiology and treatment\",\"authors\":\"Andrea Pellagatti,&nbsp;Jacqueline Boultwood\",\"doi\":\"10.1016/j.jbior.2022.100920\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Mutations of splicing factor genes (including <em>SF3B1</em>, <em>SRSF2</em>, <em>U2AF1</em> and <em>ZRSR2</em>) occur in more than half of all patients with myelodysplastic syndromes (MDS), a heterogeneous group of myeloid neoplasms. Splicing factor mutations lead to aberrant pre-mRNA splicing of many genes, some of which have been shown in functional studies to impact on hematopoiesis and to contribute to the MDS phenotype. This clearly demonstrates that impaired spliceosome function plays an important role in MDS pathophysiology. Recent studies that harnessed the power of induced pluripotent stem cell (iPSC) and CRISPR/Cas9 gene editing technologies to generate new iPSC-based models of splicing factor mutant MDS, have further illuminated the role of key downstream target genes. The aberrantly spliced genes and the dysregulated pathways associated with splicing factor mutations in MDS represent potential new therapeutic targets. Emerging data has shown that <em>IRAK4</em> is aberrantly spliced in <em>SF3B1</em> and <em>U2AF1</em> mutant MDS, leading to hyperactivation of NF-κB signaling. Pharmacological inhibition of IRAK4 has shown efficacy in pre-clinical studies and in MDS clinical trials, with higher response rates in patients with splicing factor mutations. Our increasing knowledge of the effects of splicing factor mutations in MDS is leading to the development of new treatments that may benefit patients harboring these mutations.</p></div>\",\"PeriodicalId\":7214,\"journal\":{\"name\":\"Advances in biological regulation\",\"volume\":\"87 \",\"pages\":\"Article 100920\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"4\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Advances in biological regulation\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2212492622000604\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Biochemistry, Genetics and Molecular Biology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Advances in biological regulation","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2212492622000604","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
引用次数: 4

摘要

剪接因子基因(包括SF3B1、SRSF2、U2AF1和ZRSR2)的突变发生在一半以上的骨髓增生异常综合征(MDS)患者中,MDS是一组异质性骨髓肿瘤。剪接因子突变导致许多基因的前信使核糖核酸剪接异常,其中一些基因已在功能研究中显示影响造血并导致MDS表型。这清楚地表明剪接体功能受损在MDS的病理生理学中起着重要作用。最近的研究利用诱导多能干细胞(iPSC)和CRISPR/Cas9基因编辑技术产生了新的基于iPSC的剪接因子突变体MDS模型,进一步阐明了关键下游靶基因的作用。MDS中异常剪接的基因和与剪接因子突变相关的失调途径代表了潜在的新治疗靶点。新出现的数据表明,IRAK4在SF3B1和U2AF1突变体MDS中异常剪接,导致NF-κB信号的过度激活。IRAK4的药理学抑制在临床前研究和MDS临床试验中显示出疗效,剪接因子突变患者的应答率更高。我们对MDS中剪接因子突变影响的了解不断增加,这导致了新的治疗方法的开发,这些治疗方法可能有利于携带这些突变的患者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Splicing factor mutations in the myelodysplastic syndromes: Role of key aberrantly spliced genes in disease pathophysiology and treatment

Mutations of splicing factor genes (including SF3B1, SRSF2, U2AF1 and ZRSR2) occur in more than half of all patients with myelodysplastic syndromes (MDS), a heterogeneous group of myeloid neoplasms. Splicing factor mutations lead to aberrant pre-mRNA splicing of many genes, some of which have been shown in functional studies to impact on hematopoiesis and to contribute to the MDS phenotype. This clearly demonstrates that impaired spliceosome function plays an important role in MDS pathophysiology. Recent studies that harnessed the power of induced pluripotent stem cell (iPSC) and CRISPR/Cas9 gene editing technologies to generate new iPSC-based models of splicing factor mutant MDS, have further illuminated the role of key downstream target genes. The aberrantly spliced genes and the dysregulated pathways associated with splicing factor mutations in MDS represent potential new therapeutic targets. Emerging data has shown that IRAK4 is aberrantly spliced in SF3B1 and U2AF1 mutant MDS, leading to hyperactivation of NF-κB signaling. Pharmacological inhibition of IRAK4 has shown efficacy in pre-clinical studies and in MDS clinical trials, with higher response rates in patients with splicing factor mutations. Our increasing knowledge of the effects of splicing factor mutations in MDS is leading to the development of new treatments that may benefit patients harboring these mutations.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Advances in biological regulation
Advances in biological regulation Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
8.90
自引率
0.00%
发文量
41
审稿时长
17 days
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信