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 disti...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-11-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41954-8 |
| _version_ | 1797630112225558528 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Nikolai Schleussner |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T11:03:21Z |
| format | Article |
| id | doaj.art-89617bbfc2d9437a8c22b2474e5ec08c |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-11T11:03:21Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-89617bbfc2d9437a8c22b2474e5ec08c2023-11-12T12:22:38ZengNature PortfolioNature Communications2041-17232023-11-0114111810.1038/s41467-023-41954-8Transcriptional reprogramming by mutated IRF4 in lymphomaNikolai Schleussner0Pierre Cauchy1Vedran Franke2Maciej Giefing3Oriol Fornes4Naveen Vankadari5Salam A. Assi6Mariantonia Costanza7Marc A. Weniger8Altuna Akalin9Ioannis Anagnostopoulos10Thomas Bukur11Marco G. Casarotto12Frederik Damm13Oliver Daumke14Benjamin Edginton-White15J. Christof M. Gebhardt16Michael Grau17Stephan Grunwald18Martin-Leo Hansmann19Sylvia Hartmann20Lionel Huber21Eva Kärgel22Simone Lusatis23Daniel Noerenberg24Nadine Obier25Ulrich Pannicke26Anja Fischer27Anja Reisser28Andreas Rosenwald29Klaus Schwarz30Srinivasan Sundararaj31Andre Weilemann32Wiebke Winkler33Wendan Xu34Georg Lenz35Klaus Rajewsky36Wyeth W. Wasserman37Peter N. Cockerill38Claus Scheidereit39Reiner Siebert40Ralf Küppers41Rudolf Grosschedl42Martin Janz43Constanze Bonifer44Stephan Mathas45Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant LymphomasMax Planck Institute of Immunobiology and EpigeneticsBioinformatics and Omics Data Science Platform, Berlin Institute for Medical Systems Biology, Max-Delbrück-CenterInstitute of Human Genetics, Polish Academy of SciencesCentre for Molecular Medicine and Therapeutics, Department of Medical Genetics, BC Children′s Hospital Research Institute, University of British ColumbiaDepartment of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of MelbourneInstitute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of BirminghamMax-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant LymphomasInstitute of Cell Biology (Cancer Research), University of Duisburg-EssenBioinformatics and Omics Data Science Platform, Berlin Institute for Medical Systems Biology, Max-Delbrück-CenterInstitute of Pathology, Universität Würzburg and Comprehensive Cancer Centre Mainfranken (CCCMF)TRON gGmbH – Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität MainzResearch School of Biology, The Australian National UniversityHematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of HealthMax-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Structural BiologyInstitute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of BirminghamDepartment of Physics, Institute of Biophysics, Ulm UniversityDepartment of Physics, University of MarburgMax-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Structural BiologyFrankfurt Institute of Advanced StudiesDr. Senckenberg Institute of Pathology, Goethe University FrankfurtMax Planck Institute of Immunobiology and EpigeneticsSignal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular MedicineMax-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant LymphomasHematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of HealthMax Planck Institute of Immunobiology and EpigeneticsInstitute for Transfusion Medicine, University of UlmInstitute of Human Genetics, Ulm University and Ulm University Medical CenterDepartment of Physics, Institute of Biophysics, Ulm UniversityInstitute of Pathology, Universität Würzburg and Comprehensive Cancer Centre Mainfranken (CCCMF)Institute for Transfusion Medicine, University of UlmResearch School of Biology, The Australian National UniversityMedical Department A for Hematology, Oncology and Pneumology, University Hospital MünsterMax-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant LymphomasMedical Department A for Hematology, Oncology and Pneumology, University Hospital MünsterMedical Department A for Hematology, Oncology and Pneumology, University Hospital MünsterMax-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Immune Regulation and CancerCentre for Molecular Medicine and Therapeutics, Department of Medical Genetics, BC Children′s Hospital Research Institute, University of British ColumbiaInstitute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of BirminghamSignal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular MedicineInstitute of Human Genetics, Christian-Albrechts-University KielGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)Max Planck Institute of Immunobiology and EpigeneticsMax-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant LymphomasInstitute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of BirminghamMax-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant LymphomasAbstract 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.https://doi.org/10.1038/s41467-023-41954-8 |
| spellingShingle | 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 Transcriptional reprogramming by mutated IRF4 in lymphoma Nature Communications |
| 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 |
| url | https://doi.org/10.1038/s41467-023-41954-8 |
| work_keys_str_mv | AT nikolaischleussner transcriptionalreprogrammingbymutatedirf4inlymphoma AT pierrecauchy transcriptionalreprogrammingbymutatedirf4inlymphoma AT vedranfranke transcriptionalreprogrammingbymutatedirf4inlymphoma AT maciejgiefing transcriptionalreprogrammingbymutatedirf4inlymphoma AT oriolfornes transcriptionalreprogrammingbymutatedirf4inlymphoma AT naveenvankadari transcriptionalreprogrammingbymutatedirf4inlymphoma AT salamaassi transcriptionalreprogrammingbymutatedirf4inlymphoma AT mariantoniacostanza transcriptionalreprogrammingbymutatedirf4inlymphoma AT marcaweniger transcriptionalreprogrammingbymutatedirf4inlymphoma AT altunaakalin transcriptionalreprogrammingbymutatedirf4inlymphoma AT ioannisanagnostopoulos transcriptionalreprogrammingbymutatedirf4inlymphoma AT thomasbukur transcriptionalreprogrammingbymutatedirf4inlymphoma AT marcogcasarotto transcriptionalreprogrammingbymutatedirf4inlymphoma AT frederikdamm transcriptionalreprogrammingbymutatedirf4inlymphoma AT oliverdaumke transcriptionalreprogrammingbymutatedirf4inlymphoma AT benjaminedgintonwhite transcriptionalreprogrammingbymutatedirf4inlymphoma AT jchristofmgebhardt transcriptionalreprogrammingbymutatedirf4inlymphoma AT michaelgrau transcriptionalreprogrammingbymutatedirf4inlymphoma AT stephangrunwald transcriptionalreprogrammingbymutatedirf4inlymphoma AT martinleohansmann transcriptionalreprogrammingbymutatedirf4inlymphoma AT sylviahartmann transcriptionalreprogrammingbymutatedirf4inlymphoma AT lionelhuber transcriptionalreprogrammingbymutatedirf4inlymphoma AT evakargel transcriptionalreprogrammingbymutatedirf4inlymphoma AT simonelusatis transcriptionalreprogrammingbymutatedirf4inlymphoma AT danielnoerenberg transcriptionalreprogrammingbymutatedirf4inlymphoma AT nadineobier transcriptionalreprogrammingbymutatedirf4inlymphoma AT ulrichpannicke transcriptionalreprogrammingbymutatedirf4inlymphoma AT anjafischer transcriptionalreprogrammingbymutatedirf4inlymphoma AT anjareisser transcriptionalreprogrammingbymutatedirf4inlymphoma AT andreasrosenwald transcriptionalreprogrammingbymutatedirf4inlymphoma AT klausschwarz transcriptionalreprogrammingbymutatedirf4inlymphoma AT srinivasansundararaj transcriptionalreprogrammingbymutatedirf4inlymphoma AT andreweilemann transcriptionalreprogrammingbymutatedirf4inlymphoma AT wiebkewinkler transcriptionalreprogrammingbymutatedirf4inlymphoma AT wendanxu transcriptionalreprogrammingbymutatedirf4inlymphoma AT georglenz transcriptionalreprogrammingbymutatedirf4inlymphoma AT klausrajewsky transcriptionalreprogrammingbymutatedirf4inlymphoma AT wyethwwasserman transcriptionalreprogrammingbymutatedirf4inlymphoma AT peterncockerill transcriptionalreprogrammingbymutatedirf4inlymphoma AT clausscheidereit transcriptionalreprogrammingbymutatedirf4inlymphoma AT reinersiebert transcriptionalreprogrammingbymutatedirf4inlymphoma AT ralfkuppers transcriptionalreprogrammingbymutatedirf4inlymphoma AT rudolfgrosschedl transcriptionalreprogrammingbymutatedirf4inlymphoma AT martinjanz transcriptionalreprogrammingbymutatedirf4inlymphoma AT constanzebonifer transcriptionalreprogrammingbymutatedirf4inlymphoma AT stephanmathas transcriptionalreprogrammingbymutatedirf4inlymphoma |