The ETS transcription factor ETV6 constrains the transcriptional activity of EWS-FLI to promote Ewing sarcoma.
The ETS transcription factor ETV6 constrains the transcriptional activity of EWS-FLI to promote Ewing sarcoma.
复制标题
ETS转录因子ETV 6抑制EWS-FLI的转录活性以促进尤文肉瘤。
DOI：
10.1038/s41556-022-01059-8
复制
发表时间：
2023-02
影响因子：
21.3
通讯作者：
Stegmaier, Kimberly
中科院分区：
文献类型：
--
作者：
Lu, Diana Y. Y.;Ellegast, Jana M.;Ross, Kenneth N.;Malone, Clare F.;Lin, Shan;Mabe, Nathaniel W.;Dharia, Neekesh V.;Meyer, Ashleigh;Conway, Amy;Su, Angela H. H.;Selich-Anderson, Julia;Taslim, Cenny;Byrum, Andrea K.;Seong, Bo Kyung A.;Adane, Biniam;Gray, Nathanael S.;Rivera, Miguel N.;Lessnick, Stephen L.;Stegmaier, Kimberly
转录因子（TF）在癌症中经常发生突变。儿科癌症在全基因组范围内表现出很少的突变，但经常含有影响TF的哨兵突变，这为精确研究支持突变TF驱动的肿瘤发生的转录回路提供了背景。一个广泛相关的机制，已经获得了强烈的关注，涉及突变的TF劫持野生型谱系特异性TF的自我增强转录回路的能力。然而，目前尚不清楚这种特定类型的电路是否在所有突变TF驱动的癌症中同样重要。在这里，我们描述了一个替代的，但中央的转录机制，促进尤文肉瘤，其中约束，而不是加强，融合TF EWS-FLI的活性支持癌症的生长。我们发现，ETV 6是一个关键的TF依赖性，是特定于这种疾病，因为它，反直觉，抑制EWS-FLI的转录输出。这项工作发现了一种以前未描述的促进癌症的转录机制。来自Vakoc和Stegmaier的独立但互补的研究确定并表征了ETV 6在尤文肉瘤发展过程中抵消EWS-FLI转录活性的作用，这可能是治疗益处的目标。
Transcription factors (TFs) are frequently mutated in cancer. Paediatric cancers exhibit few mutations genome-wide but frequently harbour sentinel mutations that affect TFs, which provides a context to precisely study the transcriptional circuits that support mutant TF-driven oncogenesis. A broadly relevant mechanism that has garnered intense focus involves the ability of mutant TFs to hijack wild-type lineage-specific TFs in self-reinforcing transcriptional circuits. However, it is not known whether this specific type of circuitry is equally crucial in all mutant TF-driven cancers. Here we describe an alternative yet central transcriptional mechanism that promotes Ewing sarcoma, wherein constraint, rather than reinforcement, of the activity of the fusion TF EWS–FLI supports cancer growth. We discover that ETV6 is a crucial TF dependency that is specific to this disease because it, counter-intuitively, represses the transcriptional output of EWS–FLI. This work discovers a previously undescribed transcriptional mechanism that promotes cancer. Independent but complementary studies from Vakoc and Stegmaier identify and characterize a role for ETV6 in counteracting the transcriptional activity of EWS–FLI during Ewing sarcoma development, which may be targeted for therapeutic benefits.
登录
查看更多内容
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
弥漫性大 B 细胞淋巴瘤中超级增强子相关依赖性的发现和表征。
影响因子：
50.3
作者：
Chapuy B;McKeown MR;Lin CY;Monti S;Roemer MG;Qi J;Rahl PB;Sun HH;Yeda KT;Doench JG;Reichert E;Kung AL;Rodig SJ;Young RA;Shipp MA;Bradner JE
通讯作者：
Bradner JE
影响因子：
30.8
作者：
Dharia NV;Kugener G;Guenther LM;Malone CF;Durbin AD;Hong AL;Howard TP;Bandopadhayay P;Wechsler CS;Fung I;Warren AC;Dempster JM;Krill-Burger JM;Paolella BR;Moh P;Jha N;Tang A;Montgomery P;Boehm JS;Hahn WC;Roberts CWM;McFarland JM;Tsherniak A;Golub TR;Vazquez F;Stegmaier K
通讯作者：
Stegmaier K
影响因子：
10.5
作者：
Boulay G;Volorio A;Iyer S;Broye LC;Stamenkovic I;Riggi N;Rivera MN
通讯作者：
Rivera MN
影响因子：
50.3
作者：
Adane B;Alexe G;Seong BKA;Lu D;Hwang EE;Hnisz D;Lareau CA;Ross L;Lin S;Dela Cruz FS;Richardson M;Weintraub AS;Wang S;Iniguez AB;Dharia NV;Conway AS;Robichaud AL;Tanenbaum B;Krill-Burger JM;Vazquez F;Schenone M;Berman JN;Kung AL;Carr SA;Aryee MJ;Young RA;Crompton BD;Stegmaier K
通讯作者：
Stegmaier K