High 4E-BP1 expression associates with chromosome 8 gain and CDK4/6 sensitivity in Ewing sarcoma

Chromosome 8 (chr8) gains are common in cancer, but their contribution to tumor heterogeneity is largely unexplored. Ewing sarcoma (EwS) is defined by FET::ETS fusions with few other recurrent mutations to explain clinical diversity. In EwS, chr8 gains are the second most frequent alteration, making it an ideal model to study the relevance of chr8 gains in an otherwise silent genomic context. We report that chr8 gain-driven expression patterns correlate with poor overall survival of patients with EwS. This effect is mainly mediated by increased expression of the translation initiation factor binding protein 4E-BP1, encoded by EIF4EBP1 on chr8. Among all chr8-encoded genes, EIF4EBP1 expression showed the strongest association with poor survival and correlated with chr8 gains in EwS tumors. Similar findings emerged across multiple cancer entities in The Cancer Genome Atlas. Multiomics profiling revealed that 4E-BP1 orchestrates a pro-proliferative proteomic network. Silencing 4E-BP1 reduced proliferation, clonogenicity, spheroidal growth in vitro, and tumor growth in vivo. Drug screens demonstrated that high 4E-BP1 expression sensitizes EwS to pharmacological CDK4/6-inhibition. Chr8 gains and elevated 4E-BP1 emerge as prognostic biomarkers in EwS, with poor outcomes driven by 4E-BP1-mediated pro-proliferative networks that sensitize tumors to CDK4/6 inhibitors. Testing for chr8 gains may enhance risk stratification and therapy in EwS and other cancers.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-10-16
DOI
https://doi.org/10.1172/jci187627
Primary Topic
Pancreatic and Hepatic Oncology Research
Type
article
Field-Weighted Citation Impact
0.00

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article

High 4E-BP1 expression associates with chromosome 8 gain and CDK4/6 sensitivity in Ewing sarcoma

Tilman L. B. Hoelting, Rainer Will, Cornelius M. Funk, Ina Oehme et al.
Journal of Clinical Investigation
Pancreatic and Hepatic Oncology Research
article

High 4E-BP1 expression associates with chromosome 8 gain and CDK4/6 sensitivity in Ewing sarcoma

Tilman L. B. Hoelting, Rainer Will, Cornelius M. Funk, Ina Oehme, Florencia Cidre‐Aranaz, Wolfgang Hartmann, Roland Imle, Heike Peterziel, Julian Musa, Florian H. Geyer, Franziska Willis, Shunya Ohmura, A. Katharina Ceranski, Stefan M. Pfister, Martin Schneider, Gabriel Leprivier, Uta Dirksen, Anna C. Ehlers, Ana Banito, Laura Romero‐Pérez, Andrey Loboda, Angelina Yershova, Felix Sahm, Maximilian M. L. Knott, Javier Alonso, Martin F. Orth, Ana Méndez‐Echevarría, Karim Aljakouch, Jeroen Krijgsveld, Endrit Vinca, Jana Siebenlist, Felina Zahnow, Jing Li, Olaf Witt, Thomas G.P. Grünewald
article en

Abstract

Chromosome 8 (chr8) gains are common in cancer, but their contribution to tumor heterogeneity is largely unexplored. Ewing sarcoma (EwS) is defined by FET::ETS fusions with few other recurrent mutations to explain clinical diversity. In EwS, chr8 gains are the second most frequent alteration, making it an ideal model to study the relevance of chr8 gains in an otherwise silent genomic context. We report that chr8 gain-driven expression patterns correlate with poor overall survival of patients with EwS. This effect is mainly mediated by increased expression of the translation initiation factor binding protein 4E-BP1, encoded by EIF4EBP1 on chr8. Among all chr8-encoded genes, EIF4EBP1 expression showed the strongest association with poor survival and correlated with chr8 gains in EwS tumors. Similar findings emerged across multiple cancer entities in The Cancer Genome Atlas. Multiomics profiling revealed that 4E-BP1 orchestrates a pro-proliferative proteomic network. Silencing 4E-BP1 reduced proliferation, clonogenicity, spheroidal growth in vitro, and tumor growth in vivo. Drug screens demonstrated that high 4E-BP1 expression sensitizes EwS to pharmacological CDK4/6-inhibition. Chr8 gains and elevated 4E-BP1 emerge as prognostic biomarkers in EwS, with poor outcomes driven by 4E-BP1-mediated pro-proliferative networks that sensitize tumors to CDK4/6 inhibitors. Testing for chr8 gains may enhance risk stratification and therapy in EwS and other cancers.

Journal of Clinical InvestigationVol. 135(24)
German Cancer Research Center (DE), Heidelberg University (DE), Universitätsklinikum Gießen und Marburg (DE), Hospital Universitario La Paz (ES), Instituto de Salud Carlos III (ES), University Hospital Heidelberg (DE), LMU Klinikum (DE), Düsseldorf University Hospital (DE), University Hospital Münster (DE), National Center for Tumor Diseases (DE), Hopp Children's Cancer Center Heidelberg (DE), Essen University Hospital (DE), Institute of Solid Mechanics (RO), Instituto de Biomedicina de Sevilla (ES), Max Planck Institute of Psychiatry (DE), DKFZ-ZMBH Alliance (DE), Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE), Hospital Universitario Virgen del Rocío (ES), Instituto de Investigación de Enfermedades Raras (ES), West German Heart and Vascular Center Essen (DE), Heinrich Heine University Düsseldorf (DE), Universidad de Sevilla (ES), Ludwig-Maximilians-Universität München (DE)
Deutsches Krebsforschungszentrum, European Commission, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, China Scholarship Council, Deutsche Krebshilfe, Asociación Pablo Ugarte, Dr. Rolf M. Schwiete Stiftung, Instituto de Salud Carlos III
Openalex Percentile: Top 60%
Pancreatic and Hepatic Oncology Research
DOIOpen Access PDFOpenAlex
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