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; Stephan Mathas

doi:10.1038/s41467-023-41954-8

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 HansmannSylvia 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, Stephan Mathas^*

^*Corresponding author for this work

Cancer and Genomic Sciences

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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.

Original language	English
Article number	6947
Number of pages	18
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-41954-8
Publication status	Published - 7 Nov 2023

Bibliographical note

Funding:
Open Access funding enabled and organized by Projekt DEAL.

Copyright:
© 2023. The Author(s).

Keywords

Humans
Interferon Regulatory Factors/genetics
Lymphoma/genetics
Gene Expression Regulation
B-Lymphocytes/metabolism
DNA

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Schleussner, N., Cauchy, P., Franke, V., Giefing, M., Fornes, O., Vankadari, N., Assi, S. A., Costanza, M., Weniger, M. A., Akalin, A., Anagnostopoulos, I., Bukur, T., Casarotto, M. G., Damm, F., Daumke, O., Edginton-White, B., Gebhardt, J. C. M., Grau, M., Grunwald, S., ... Mathas, S. (2023). Transcriptional reprogramming by mutated IRF4 in lymphoma. Nature Communications, 14(1), Article 6947. https://doi.org/10.1038/s41467-023-41954-8

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title = "Transcriptional reprogramming by mutated IRF4 in lymphoma",

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.",

keywords = "Humans, Interferon Regulatory Factors/genetics, Lymphoma/genetics, Gene Expression Regulation, B-Lymphocytes/metabolism, DNA",

author = "Nikolai Schleussner and Pierre Cauchy and Vedran Franke and Maciej Giefing and Oriol Fornes and Naveen Vankadari and Assi, {Salam A} and Mariantonia Costanza and Weniger, {Marc A} and Altuna Akalin and Ioannis Anagnostopoulos and Thomas Bukur and Casarotto, {Marco G} and Frederik Damm and Oliver Daumke and Benjamin Edginton-White and Gebhardt, {J Christof M} and Michael Grau and Stephan Grunwald and Martin-Leo Hansmann and Sylvia Hartmann and Lionel Huber and Eva K{\"a}rgel and Simone Lusatis and Daniel Noerenberg and Nadine Obier and Ulrich Pannicke and Anja Fischer and Anja Reisser and Andreas Rosenwald and Klaus Schwarz and Srinivasan Sundararaj and Andre Weilemann and Wiebke Winkler and Wendan Xu and Georg Lenz and Klaus Rajewsky and Wasserman, {Wyeth W} and Cockerill, {Peter N} and Claus Scheidereit and Reiner Siebert and Ralf K{\"u}ppers and Rudolf Grosschedl and Martin Janz and Constanze Bonifer and Stephan Mathas",

note = "Funding: Open Access funding enabled and organized by Projekt DEAL. Copyright: {\textcopyright} 2023. The Author(s).",

year = "2023",

month = nov,

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doi = "10.1038/s41467-023-41954-8",

language = "English",

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journal = "Nature Communications",

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Schleussner, N, Cauchy, P, Franke, V, Giefing, M, Fornes, O, Vankadari, N, Assi, SA, Costanza, M, Weniger, MA, Akalin, A, Anagnostopoulos, I, Bukur, T, Casarotto, MG, Damm, F, Daumke, O, Edginton-White, B, Gebhardt, JCM, Grau, M, Grunwald, S, Hansmann, M-L, Hartmann, S, Huber, L, Kärgel, E, Lusatis, S, Noerenberg, D, Obier, N, Pannicke, U, Fischer, A, Reisser, A, Rosenwald, A, Schwarz, K, Sundararaj, S, Weilemann, A, Winkler, W, Xu, W, Lenz, G, Rajewsky, K, Wasserman, WW, Cockerill, PN, Scheidereit, C, Siebert, R, Küppers, R, Grosschedl, R, Janz, M, Bonifer, C & Mathas, S 2023, 'Transcriptional reprogramming by mutated IRF4 in lymphoma', Nature Communications, vol. 14, no. 1, 6947. https://doi.org/10.1038/s41467-023-41954-8

TY - JOUR

T1 - Transcriptional reprogramming by mutated IRF4 in lymphoma

AU - Schleussner, Nikolai

AU - Cauchy, Pierre

AU - Franke, Vedran

AU - Giefing, Maciej

AU - Fornes, Oriol

AU - Vankadari, Naveen

AU - Assi, Salam A

AU - Costanza, Mariantonia

AU - Weniger, Marc A

AU - Akalin, Altuna

AU - Anagnostopoulos, Ioannis

AU - Bukur, Thomas

AU - Casarotto, Marco G

AU - Damm, Frederik

AU - Daumke, Oliver

AU - Edginton-White, Benjamin

AU - Gebhardt, J Christof M

AU - Grau, Michael

AU - Grunwald, Stephan

AU - Hansmann, Martin-Leo

AU - Hartmann, Sylvia

AU - Huber, Lionel

AU - Kärgel, Eva

AU - Lusatis, Simone

AU - Noerenberg, Daniel

AU - Obier, Nadine

AU - Pannicke, Ulrich

AU - Fischer, Anja

AU - Reisser, Anja

AU - Rosenwald, Andreas

AU - Schwarz, Klaus

AU - Sundararaj, Srinivasan

AU - Weilemann, Andre

AU - Winkler, Wiebke

AU - Xu, Wendan

AU - Lenz, Georg

AU - Rajewsky, Klaus

AU - Wasserman, Wyeth W

AU - Cockerill, Peter N

AU - Scheidereit, Claus

AU - Siebert, Reiner

AU - Küppers, Ralf

AU - Grosschedl, Rudolf

AU - Janz, Martin

AU - Bonifer, Constanze

AU - Mathas, Stephan

PY - 2023/11/7

Y1 - 2023/11/7

N2 - 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.

AB - 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.

KW - Humans

KW - Interferon Regulatory Factors/genetics

KW - Lymphoma/genetics

KW - Gene Expression Regulation

KW - B-Lymphocytes/metabolism

KW - DNA

U2 - 10.1038/s41467-023-41954-8

DO - 10.1038/s41467-023-41954-8

M3 - Article

C2 - 37935654

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6947

ER -

Transcriptional reprogramming by mutated IRF4 in lymphoma

Abstract

Bibliographical note

Keywords

UN SDGs

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Cite this