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

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; Olivier Delattre

doi:10.1016/j.molcel.2022.04.019

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

Mol Cell. 2022 Jul 7;82(13):2458-2471.e9. doi: 10.1016/j.molcel.2022.04.019. Epub 2022 May 11.

Authors

Julien Vibert¹, Olivier Saulnier², Céline Collin², Floriane Petit², Kyra J E Borgman³, Jérômine Vigneau², Maud Gautier², Sakina Zaidi², Gaëlle Pierron⁴, Sarah Watson⁵, Nadège Gruel⁶, Clémence Hénon⁷, Sophie Postel-Vinay⁸, Marc Deloger⁹, Virginie Raynal¹⁰, Sylvain Baulande¹⁰, Karine Laud-Duval², Véronique Hill², Sandrine Grossetête², Florent Dingli¹¹, Damarys Loew¹¹, Jacob Torrejon¹², Olivier Ayrault¹², Martin F Orth¹³, Thomas G P Grünewald¹⁴, Didier Surdez², Antoine Coulon³, Joshua J Waterfall¹⁵, Olivier Delattre¹⁶

Affiliations

¹ INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France; INSERM U830, Integrative Functional Genomics of Cancer Lab, PSL Research University, Institut Curie Research Center, Paris, France; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris, France.
² INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France.
³ Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR 3664, Laboratoire Dynamique du Noyau, 75005 Paris, France; Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR168, Laboratoire Physico Chimie Curie, 75005 Paris, France.
⁴ Unité de Génétique Somatique, Service d'oncogénétique, Institut Curie, Centre Hospitalier, Paris, France.
⁵ INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France; Medical Oncology Department, PSL Research University, Institut Curie Hospital, Paris, France.
⁶ INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris, France.
⁷ ATIP-Avenir group, Inserm Unit U981, Gustave Roussy, Villejuif, France.
⁸ ATIP-Avenir group, Inserm Unit U981, Gustave Roussy, Villejuif, France; Drug Development Department, DITEP, Gustave Roussy, Villejuif, France.
⁹ Bioinformatics and Computational Systems Biology of Cancer, PSL Research University, Mines Paris Tech, INSERM U900, Paris, France.
¹⁰ Institut Curie Genomics of Excellence (ICGex) Platform, PSL Research University, Institut Curie Research Center, Paris, France.
¹¹ Laboratoire de Spectrométrie de Masse Protéomique, PSL Research University, Institut Curie Research Center, Paris, France.
¹² Institut Curie, CNRS UMR3347, INSERM, PSL Research University, Orsay, France; CNRS UMR 3347, INSERM U1021, Université Paris Sud, Université Paris-Saclay, Orsay, France.
¹³ Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
¹⁴ Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany; Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
¹⁵ INSERM U830, Integrative Functional Genomics of Cancer Lab, PSL Research University, Institut Curie Research Center, Paris, France; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris, France. Electronic address: [email protected].
¹⁶ INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France; Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR 3664, Laboratoire Dynamique du Noyau, 75005 Paris, France. Electronic address: [email protected].

PMID: 35550257
DOI: 10.1016/j.molcel.2022.04.019

Abstract

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.

Keywords: chimeric transcription factors; long non-coding RNAs; sarcomas; tumor-specific peptides; tumor-specific transcripts.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Carcinogenesis* / genetics
Cell Line, Tumor
Gene Expression Regulation, Neoplastic* / genetics
Gene Silencing
Genome / genetics
Genomics
Humans
Oncogene Proteins, Fusion* / genetics
Oncogene Proteins, Fusion* / metabolism
Oncogenes / genetics
Proto-Oncogene Protein c-fli-1* / genetics
Proto-Oncogene Protein c-fli-1* / metabolism
Sarcoma, Ewing / genetics
Sarcoma, Ewing / metabolism
Sarcoma, Ewing / pathology
Transcription Factors* / genetics
Transcription, Genetic / genetics

Substances

Oncogene Proteins, Fusion
Proto-Oncogene Protein c-fli-1
Transcription Factors