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Transcriptional reprogramming by mutated IRF4 in lymphoma
Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mecha...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10630337/ https://www.ncbi.nlm.nih.gov/pubmed/37935654 http://dx.doi.org/10.1038/s41467-023-41954-8 |
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author | Schleussner, Nikolai Cauchy, Pierre Franke, Vedran Giefing, Maciej Fornes, Oriol Vankadari, Naveen Assi, Salam A. Costanza, Mariantonia Weniger, Marc A. Akalin, Altuna Anagnostopoulos, Ioannis Bukur, Thomas Casarotto, Marco G. Damm, Frederik Daumke, Oliver Edginton-White, Benjamin Gebhardt, J. Christof M. Grau, Michael Grunwald, Stephan Hansmann, Martin-Leo Hartmann, Sylvia Huber, Lionel Kärgel, Eva Lusatis, Simone Noerenberg, Daniel Obier, Nadine Pannicke, Ulrich Fischer, Anja Reisser, Anja Rosenwald, Andreas Schwarz, Klaus Sundararaj, Srinivasan Weilemann, Andre Winkler, Wiebke Xu, Wendan Lenz, Georg Rajewsky, Klaus Wasserman, Wyeth W. Cockerill, Peter N. Scheidereit, Claus Siebert, Reiner Küppers, Ralf Grosschedl, Rudolf Janz, Martin Bonifer, Constanze Mathas, Stephan |
author_facet | Schleussner, Nikolai Cauchy, Pierre Franke, Vedran Giefing, Maciej Fornes, Oriol Vankadari, Naveen Assi, Salam A. Costanza, Mariantonia Weniger, Marc A. Akalin, Altuna Anagnostopoulos, Ioannis Bukur, Thomas Casarotto, Marco G. Damm, Frederik Daumke, Oliver Edginton-White, Benjamin Gebhardt, J. Christof M. Grau, Michael Grunwald, Stephan Hansmann, Martin-Leo Hartmann, Sylvia Huber, Lionel Kärgel, Eva Lusatis, Simone Noerenberg, Daniel Obier, Nadine Pannicke, Ulrich Fischer, Anja Reisser, Anja Rosenwald, Andreas Schwarz, Klaus Sundararaj, Srinivasan Weilemann, Andre Winkler, Wiebke Xu, Wendan Lenz, Georg Rajewsky, Klaus Wasserman, Wyeth W. Cockerill, Peter N. Scheidereit, Claus Siebert, Reiner Küppers, Ralf Grosschedl, Rudolf Janz, Martin Bonifer, Constanze Mathas, Stephan |
author_sort | Schleussner, Nikolai |
collection | PubMed |
description | Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma. It is caused by a recurrent somatic missense mutation c.295 T > C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF CEs. IRF4-C99R thoroughly modifies IRF4 function by blocking IRF4-dependent plasma cell induction, and up-regulates disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single mutation causes a complex switch of TF specificity and gene regulation and open the perspective to specifically block the neomorphic DNA-binding activities of a mutant TF. |
format | Online Article Text |
id | pubmed-10630337 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-106303372023-11-07 Transcriptional reprogramming by mutated IRF4 in lymphoma Schleussner, Nikolai Cauchy, Pierre Franke, Vedran Giefing, Maciej Fornes, Oriol Vankadari, Naveen Assi, Salam A. Costanza, Mariantonia Weniger, Marc A. Akalin, Altuna Anagnostopoulos, Ioannis Bukur, Thomas Casarotto, Marco G. Damm, Frederik Daumke, Oliver Edginton-White, Benjamin Gebhardt, J. Christof M. Grau, Michael Grunwald, Stephan Hansmann, Martin-Leo Hartmann, Sylvia Huber, Lionel Kärgel, Eva Lusatis, Simone Noerenberg, Daniel Obier, Nadine Pannicke, Ulrich Fischer, Anja Reisser, Anja Rosenwald, Andreas Schwarz, Klaus Sundararaj, Srinivasan Weilemann, Andre Winkler, Wiebke Xu, Wendan Lenz, Georg Rajewsky, Klaus Wasserman, Wyeth W. Cockerill, Peter N. Scheidereit, Claus Siebert, Reiner Küppers, Ralf Grosschedl, Rudolf Janz, Martin Bonifer, Constanze Mathas, Stephan Nat Commun Article Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma. It is caused by a recurrent somatic missense mutation c.295 T > C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF CEs. IRF4-C99R thoroughly modifies IRF4 function by blocking IRF4-dependent plasma cell induction, and up-regulates disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single mutation causes a complex switch of TF specificity and gene regulation and open the perspective to specifically block the neomorphic DNA-binding activities of a mutant TF. Nature Publishing Group UK 2023-11-07 /pmc/articles/PMC10630337/ /pubmed/37935654 http://dx.doi.org/10.1038/s41467-023-41954-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Schleussner, Nikolai Cauchy, Pierre Franke, Vedran Giefing, Maciej Fornes, Oriol Vankadari, Naveen Assi, Salam A. Costanza, Mariantonia Weniger, Marc A. Akalin, Altuna Anagnostopoulos, Ioannis Bukur, Thomas Casarotto, Marco G. Damm, Frederik Daumke, Oliver Edginton-White, Benjamin Gebhardt, J. Christof M. Grau, Michael Grunwald, Stephan Hansmann, Martin-Leo Hartmann, Sylvia Huber, Lionel Kärgel, Eva Lusatis, Simone Noerenberg, Daniel Obier, Nadine Pannicke, Ulrich Fischer, Anja Reisser, Anja Rosenwald, Andreas Schwarz, Klaus Sundararaj, Srinivasan Weilemann, Andre Winkler, Wiebke Xu, Wendan Lenz, Georg Rajewsky, Klaus Wasserman, Wyeth W. Cockerill, Peter N. Scheidereit, Claus Siebert, Reiner Küppers, Ralf Grosschedl, Rudolf Janz, Martin Bonifer, Constanze Mathas, Stephan Transcriptional reprogramming by mutated IRF4 in lymphoma |
title | Transcriptional reprogramming by mutated IRF4 in lymphoma |
title_full | Transcriptional reprogramming by mutated IRF4 in lymphoma |
title_fullStr | Transcriptional reprogramming by mutated IRF4 in lymphoma |
title_full_unstemmed | Transcriptional reprogramming by mutated IRF4 in lymphoma |
title_short | Transcriptional reprogramming by mutated IRF4 in lymphoma |
title_sort | transcriptional reprogramming by mutated irf4 in lymphoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10630337/ https://www.ncbi.nlm.nih.gov/pubmed/37935654 http://dx.doi.org/10.1038/s41467-023-41954-8 |
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