Transcriptional reprogramming by mutated IRF4 in lymphoma

Nikolai Schleussner, Pierre Cauchy, Vedran Franke, Maciej Giefing, Oriol Fornes, Naveen Vankadari, Salam A. Assi, Mariantonia Costanza, Marc A. Weniger, Altuna Akalin, Ioannis Anagnostopoulos, Thomas Bukur, Marco G. Casarotto, Frederik Damm, Oliver Daumke, Benjamin Edginton-White, J. Christof M. Gebhardt, Michael Grau, Stephan Grunwald, Martin-Leo Hansmann, Sylvia Hartmann, Lionel Huber, Eva Kärgel, Simone Lusatis, Daniel Noerenberg, Nadine Obier, Ulrich Pannicke, Anja Fischer, Anja Reisser, Andreas Rosenwald, Klaus Schwarz, Srinivasan Sundararaj, Andre Weilemann, Wiebke Winkler, Wendan Xu, Georg Lenz, Klaus Rajewsky, Wyeth W. Wasserman, Peter N. Cockerill, Claus Scheidereit, Reiner Siebert, Ralf Küppers, Rudolf Grosschedl, Martin Janz, Constanze Bonifer and Stephan Mathas ()
Additional contact information
Nikolai Schleussner: Biology of Malignant Lymphomas
Pierre Cauchy: Max Planck Institute of Immunobiology and Epigenetics
Vedran Franke: Max-Delbrück-Center
Maciej Giefing: Polish Academy of Sciences
Oriol Fornes: University of British Columbia
Naveen Vankadari: The University of Melbourne
Salam A. Assi: University of Birmingham
Mariantonia Costanza: Biology of Malignant Lymphomas
Marc A. Weniger: University of Duisburg-Essen
Altuna Akalin: Max-Delbrück-Center
Ioannis Anagnostopoulos: Universität Würzburg and Comprehensive Cancer Centre Mainfranken (CCCMF)
Thomas Bukur: TRON gGmbH – Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Marco G. Casarotto: The Australian National University
Frederik Damm: Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
Oliver Daumke: Structural Biology
Benjamin Edginton-White: University of Birmingham
J. Christof M. Gebhardt: Ulm University
Michael Grau: University of Marburg
Stephan Grunwald: Structural Biology
Martin-Leo Hansmann: Frankfurt Institute of Advanced Studies
Sylvia Hartmann: Goethe University Frankfurt
Lionel Huber: Max Planck Institute of Immunobiology and Epigenetics
Eva Kärgel: Max-Delbrück-Center for Molecular Medicine
Simone Lusatis: Biology of Malignant Lymphomas
Daniel Noerenberg: Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
Nadine Obier: Max Planck Institute of Immunobiology and Epigenetics
Ulrich Pannicke: University of Ulm
Anja Fischer: Ulm University and Ulm University Medical Center
Anja Reisser: Ulm University
Andreas Rosenwald: Universität Würzburg and Comprehensive Cancer Centre Mainfranken (CCCMF)
Klaus Schwarz: University of Ulm
Srinivasan Sundararaj: The Australian National University
Andre Weilemann: University Hospital Münster
Wiebke Winkler: Biology of Malignant Lymphomas
Wendan Xu: University Hospital Münster
Georg Lenz: University Hospital Münster
Klaus Rajewsky: Immune Regulation and Cancer
Wyeth W. Wasserman: University of British Columbia
Peter N. Cockerill: University of Birmingham
Claus Scheidereit: Max-Delbrück-Center for Molecular Medicine
Reiner Siebert: Christian-Albrechts-University Kiel
Ralf Küppers: German Cancer Research Center (DKFZ)
Rudolf Grosschedl: Max Planck Institute of Immunobiology and Epigenetics
Martin Janz: Biology of Malignant Lymphomas
Constanze Bonifer: University of Birmingham
Stephan Mathas: Biology of Malignant Lymphomas

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-41954-8

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