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Oncogenic chimeric transcription factors drive tumor-specific transcription, processing, and translation of silent genomic regions

Many cancers are characterized by gene fusions encoding oncogenic chimeric transcription factors (TFs) such as EWS::FLI1 in Ewing sarcoma (EwS). Here, we find that EWS::FLI1 induces the robust expression of a specific set of novel spliced and polyadenylated transcripts within otherwise transcription...

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Main Authors: Vibert, Julien (Author) , Saulnier, Olivier (Author) , Collin, Céline (Author) , Petit, Floriane (Author) , Borgman, Kyra J. E. (Author) , Vigneau, Jérômine (Author) , Gautier, Maud (Author) , Zaidi, Sakina (Author) , Pierron, Gaëlle (Author) , Watson, Sarah (Author) , Gruel, Nadège (Author) , Hénon, Clémence (Author) , Postel-Vinay, Sophie (Author) , Deloger, Marc (Author) , Raynal, Virginie (Author) , Baulande, Sylvain (Author) , Laud-Duval, Karine (Author) , Hill, Véronique (Author) , Grossetête, Sandrine (Author) , Dingli, Florent (Author) , Loew, Damarys (Author) , Torrejon, Jacob (Author) , Ayrault, Olivier (Author) , Orth, Martin F. (Author) , Grünewald, Thomas G. P. (Author) , Surdez, Didier (Author) , Coulon, Antoine (Author) , Waterfall, Joshua J. (Author) , Delattre, Olivier (Author)
Format: Article (Journal)
Language:English
Published: July 7, 2022
In: Molecular cell
Year: 2022, Volume: 82, Issue: 13, Pages: 2458-2471
ISSN:1097-4164
DOI:10.1016/j.molcel.2022.04.019
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.molcel.2022.04.019
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1097276522003823
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Author Notes:Julien Vibert, Olivier Saulnier, Céline Collin, Floriane Petit, Kyra J. E. Borgman, Jérômine Vigneau, Maud Gautier, Sakina Zaidi, Gaëlle Pierron, Sarah Watson, Nadège Gruel, Clémence Hénon, Sophie Postel-Vinay, Marc Deloger, Virginie Raynal, Sylvain Baulande, Karine Laud-Duval, Véronique Hill, Sandrine Grossetête, Florent Dingli, Damarys Loew, Jacob Torrejon, Olivier Ayrault, Martin F. Orth, Thomas G.P. Grünewald, Didier Surdez, Antoine Coulon, Joshua J. Waterfall, and Olivier Delattre
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Summary:Many cancers are characterized by gene fusions encoding oncogenic chimeric transcription factors (TFs) such as EWS::FLI1 in Ewing sarcoma (EwS). Here, we find that EWS::FLI1 induces the robust expression of a specific set of novel spliced and polyadenylated transcripts within otherwise transcriptionally silent regions of the genome. These neogenes (NGs) are virtually undetectable in large collections of normal tissues or non-EwS tumors and can be silenced by CRISPR interference at regulatory EWS::FLI1-bound microsatellites. Ribosome profiling and proteomics further show that some NGs are translated into highly EwS-specific peptides. More generally, we show that hundreds of NGs can be detected in diverse cancers characterized by chimeric TFs. Altogether, this study identifies the transcription, processing, and translation of novel, specific, highly expressed multi-exonic transcripts from otherwise silent regions of the genome as a new activity of aberrant TFs in cancer.
Item Description:Gesehen am 14.09.2022
Physical Description:Online Resource
ISSN:1097-4164
DOI:10.1016/j.molcel.2022.04.019

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