EZH2在CML中通过抑制剪接因子调节mRNA剪接并发挥部分致癌功能

IF 12.8 1区 医学 Q1 HEMATOLOGY Leukemia Pub Date : 2025-01-07 DOI:10.1038/s41375-024-02509-y
Reinhard Brunmeir, Li Ying, Junli Yan, Yan Ting Hee, Baohong Lin, Harvinder Kaur, Qiao Zheng Leong, Wei Wen Teo, Gerald Choong, Wei-Ying Jen, Liang Piu Koh, Lip Kun Tan, Esther Chan, Melissa Ooi, Henry Yang, Wee Joo Chng
{"title":"EZH2在CML中通过抑制剪接因子调节mRNA剪接并发挥部分致癌功能","authors":"Reinhard Brunmeir, Li Ying, Junli Yan, Yan Ting Hee, Baohong Lin, Harvinder Kaur, Qiao Zheng Leong, Wei Wen Teo, Gerald Choong, Wei-Ying Jen, Liang Piu Koh, Lip Kun Tan, Esther Chan, Melissa Ooi, Henry Yang, Wee Joo Chng","doi":"10.1038/s41375-024-02509-y","DOIUrl":null,"url":null,"abstract":"<p>The polycomb protein EZH2 is up-regulated in Chronic Myeloid Leukaemia (CML) and associated with transcriptional reprogramming. Here we tested whether EZH2 might also act as a modulator of the mRNA splicing landscape to elicit its oncogenic function in CML. We treated CML cell lines with EZH2 inhibitors and detected differential splicing of several hundreds of events, potentially caused by the transcriptional regulation of splicing factors. Amongst those genes, CELF2 was identified as a candidate to mediate part of the EZH2 inhibitor induced phenotype. Upon over-expression, we observed (1) reduced cell growth, viability, and colony formation of CML cell lines, (2) a change in the splicing landscape, partially overlapping with EZH2 mediated changes, (3) the down-regulation of MYC signalling. Importantly, these findings were successfully validated in a cohort of CML patient samples, confirming the role of CELF2 as EZH2-regulated tumour-suppressor, contributing to the severe splicing de-regulation present in CML. Based on this we propose that EZH2 exerts part of its oncogenic function in CML through the transcriptional repression of splicing factors. Finally, analysis of publicly available datasets suggests that splicing modulation by EZH2 might not be restricted to CML.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"125 1","pages":""},"PeriodicalIF":12.8000,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"EZH2 modulates mRNA splicing and exerts part of its oncogenic function through repression of splicing factors in CML\",\"authors\":\"Reinhard Brunmeir, Li Ying, Junli Yan, Yan Ting Hee, Baohong Lin, Harvinder Kaur, Qiao Zheng Leong, Wei Wen Teo, Gerald Choong, Wei-Ying Jen, Liang Piu Koh, Lip Kun Tan, Esther Chan, Melissa Ooi, Henry Yang, Wee Joo Chng\",\"doi\":\"10.1038/s41375-024-02509-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>The polycomb protein EZH2 is up-regulated in Chronic Myeloid Leukaemia (CML) and associated with transcriptional reprogramming. Here we tested whether EZH2 might also act as a modulator of the mRNA splicing landscape to elicit its oncogenic function in CML. We treated CML cell lines with EZH2 inhibitors and detected differential splicing of several hundreds of events, potentially caused by the transcriptional regulation of splicing factors. Amongst those genes, CELF2 was identified as a candidate to mediate part of the EZH2 inhibitor induced phenotype. Upon over-expression, we observed (1) reduced cell growth, viability, and colony formation of CML cell lines, (2) a change in the splicing landscape, partially overlapping with EZH2 mediated changes, (3) the down-regulation of MYC signalling. Importantly, these findings were successfully validated in a cohort of CML patient samples, confirming the role of CELF2 as EZH2-regulated tumour-suppressor, contributing to the severe splicing de-regulation present in CML. Based on this we propose that EZH2 exerts part of its oncogenic function in CML through the transcriptional repression of splicing factors. Finally, analysis of publicly available datasets suggests that splicing modulation by EZH2 might not be restricted to CML.</p>\",\"PeriodicalId\":18109,\"journal\":{\"name\":\"Leukemia\",\"volume\":\"125 1\",\"pages\":\"\"},\"PeriodicalIF\":12.8000,\"publicationDate\":\"2025-01-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Leukemia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41375-024-02509-y\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Leukemia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41375-024-02509-y","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

多梳蛋白EZH2在慢性髓性白血病(CML)中上调,并与转录重编程相关。在这里,我们测试了EZH2是否也可能作为mRNA剪接景观的调节剂,从而引发其在CML中的致癌功能。我们用EZH2抑制剂处理CML细胞系,并检测到数百种不同的剪接事件,这些事件可能是由剪接因子的转录调节引起的。在这些基因中,CELF2被确定为介导部分EZH2抑制剂诱导表型的候选基因。在过表达时,我们观察到(1)CML细胞系的细胞生长、活力和集落形成降低,(2)剪接景观的变化,与EZH2介导的变化部分重叠,(3)MYC信号的下调。重要的是,这些发现在CML患者样本队列中得到了成功验证,证实了CELF2作为ezh2调节的肿瘤抑制因子的作用,有助于CML中存在的严重剪接去调节。基于此,我们提出EZH2通过对剪接因子的转录抑制在CML中发挥部分致癌功能。最后,对公开数据集的分析表明,EZH2的剪接调制可能并不局限于CML。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
EZH2 modulates mRNA splicing and exerts part of its oncogenic function through repression of splicing factors in CML

The polycomb protein EZH2 is up-regulated in Chronic Myeloid Leukaemia (CML) and associated with transcriptional reprogramming. Here we tested whether EZH2 might also act as a modulator of the mRNA splicing landscape to elicit its oncogenic function in CML. We treated CML cell lines with EZH2 inhibitors and detected differential splicing of several hundreds of events, potentially caused by the transcriptional regulation of splicing factors. Amongst those genes, CELF2 was identified as a candidate to mediate part of the EZH2 inhibitor induced phenotype. Upon over-expression, we observed (1) reduced cell growth, viability, and colony formation of CML cell lines, (2) a change in the splicing landscape, partially overlapping with EZH2 mediated changes, (3) the down-regulation of MYC signalling. Importantly, these findings were successfully validated in a cohort of CML patient samples, confirming the role of CELF2 as EZH2-regulated tumour-suppressor, contributing to the severe splicing de-regulation present in CML. Based on this we propose that EZH2 exerts part of its oncogenic function in CML through the transcriptional repression of splicing factors. Finally, analysis of publicly available datasets suggests that splicing modulation by EZH2 might not be restricted to CML.

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
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
期刊最新文献
STING mediates increased self-renewal and lineage skewing in DNMT3A-mutated hematopoietic stem/progenitor cells Distinct leukemogenic mechanism of acute promyelocytic leukemia based on genomic structure of PML::RARα Donor selection in T-cell-replete haploidentical donor peripheral blood stem cell transplantation Nelarabine in T-cell acute lymphoblastic leukemia: intracellular metabolism and molecular mode-of-action Improved prognosis of advanced-stage extranodal NK/T-cell lymphoma: results of the NKEA-Next study
×
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
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 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 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1