Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
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
_version_ 1785132128580665344
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
work_keys_str_mv AT schleussnernikolai transcriptionalreprogrammingbymutatedirf4inlymphoma
AT cauchypierre transcriptionalreprogrammingbymutatedirf4inlymphoma
AT frankevedran transcriptionalreprogrammingbymutatedirf4inlymphoma
AT giefingmaciej transcriptionalreprogrammingbymutatedirf4inlymphoma
AT fornesoriol transcriptionalreprogrammingbymutatedirf4inlymphoma
AT vankadarinaveen transcriptionalreprogrammingbymutatedirf4inlymphoma
AT assisalama transcriptionalreprogrammingbymutatedirf4inlymphoma
AT costanzamariantonia transcriptionalreprogrammingbymutatedirf4inlymphoma
AT wenigermarca transcriptionalreprogrammingbymutatedirf4inlymphoma
AT akalinaltuna transcriptionalreprogrammingbymutatedirf4inlymphoma
AT anagnostopoulosioannis transcriptionalreprogrammingbymutatedirf4inlymphoma
AT bukurthomas transcriptionalreprogrammingbymutatedirf4inlymphoma
AT casarottomarcog transcriptionalreprogrammingbymutatedirf4inlymphoma
AT dammfrederik transcriptionalreprogrammingbymutatedirf4inlymphoma
AT daumkeoliver transcriptionalreprogrammingbymutatedirf4inlymphoma
AT edgintonwhitebenjamin transcriptionalreprogrammingbymutatedirf4inlymphoma
AT gebhardtjchristofm transcriptionalreprogrammingbymutatedirf4inlymphoma
AT graumichael transcriptionalreprogrammingbymutatedirf4inlymphoma
AT grunwaldstephan transcriptionalreprogrammingbymutatedirf4inlymphoma
AT hansmannmartinleo transcriptionalreprogrammingbymutatedirf4inlymphoma
AT hartmannsylvia transcriptionalreprogrammingbymutatedirf4inlymphoma
AT huberlionel transcriptionalreprogrammingbymutatedirf4inlymphoma
AT kargeleva transcriptionalreprogrammingbymutatedirf4inlymphoma
AT lusatissimone transcriptionalreprogrammingbymutatedirf4inlymphoma
AT noerenbergdaniel transcriptionalreprogrammingbymutatedirf4inlymphoma
AT obiernadine transcriptionalreprogrammingbymutatedirf4inlymphoma
AT pannickeulrich transcriptionalreprogrammingbymutatedirf4inlymphoma
AT fischeranja transcriptionalreprogrammingbymutatedirf4inlymphoma
AT reisseranja transcriptionalreprogrammingbymutatedirf4inlymphoma
AT rosenwaldandreas transcriptionalreprogrammingbymutatedirf4inlymphoma
AT schwarzklaus transcriptionalreprogrammingbymutatedirf4inlymphoma
AT sundararajsrinivasan transcriptionalreprogrammingbymutatedirf4inlymphoma
AT weilemannandre transcriptionalreprogrammingbymutatedirf4inlymphoma
AT winklerwiebke transcriptionalreprogrammingbymutatedirf4inlymphoma
AT xuwendan transcriptionalreprogrammingbymutatedirf4inlymphoma
AT lenzgeorg transcriptionalreprogrammingbymutatedirf4inlymphoma
AT rajewskyklaus transcriptionalreprogrammingbymutatedirf4inlymphoma
AT wassermanwyethw transcriptionalreprogrammingbymutatedirf4inlymphoma
AT cockerillpetern transcriptionalreprogrammingbymutatedirf4inlymphoma
AT scheidereitclaus transcriptionalreprogrammingbymutatedirf4inlymphoma
AT siebertreiner transcriptionalreprogrammingbymutatedirf4inlymphoma
AT kuppersralf transcriptionalreprogrammingbymutatedirf4inlymphoma
AT grosschedlrudolf transcriptionalreprogrammingbymutatedirf4inlymphoma
AT janzmartin transcriptionalreprogrammingbymutatedirf4inlymphoma
AT boniferconstanze transcriptionalreprogrammingbymutatedirf4inlymphoma
AT mathasstephan transcriptionalreprogrammingbymutatedirf4inlymphoma