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| Item Type: | Article |
|---|---|
| Title: | Transcriptional reprogramming by mutated IRF4 in lymphoma |
| Creators: |
Schleussner, N.  ORCID: https://orcid.org/0009-0001-3549-5600, Cauchy, P. ORCID: https://orcid.org/0000-0002-0659-0799, Franke, V. ORCID: https://orcid.org/0000-0003-3606-6792, Giefing, M., Fornes, O. ORCID: https://orcid.org/0000-0002-5969-3054, Vankadari, N. ORCID: https://orcid.org/0000-0001-9363-080X, Assi, S.A., Costanza, M. ORCID: https://orcid.org/0000-0002-8959-1083, Weniger, M.A., Akalin, A. ORCID: https://orcid.org/0000-0002-0468-0117, Anagnostopoulos, I. ORCID: https://orcid.org/0000-0002-5043-6043, Bukur, T., Casarotto, M.G. ORCID: https://orcid.org/0000-0002-0571-7671, Damm, F. ORCID: https://orcid.org/0000-0001-5553-1173, Daumke, O. ORCID: https://orcid.org/0000-0002-6190-1414, Edginton-White, B., Gebhardt, J.C.M. ORCID: https://orcid.org/0000-0003-1900-600X, Grau, M., Grunwald, S. ORCID: https://orcid.org/0000-0003-3978-6277, Hansmann, M.L., Hartmann, S. ORCID: https://orcid.org/0000-0003-3424-1091, Huber, L., Kärgel, E., Lusatis, S., Noerenberg, D., Obier, N., Pannicke, U. ORCID: https://orcid.org/0000-0002-0929-1794, Fischer, A. ORCID: https://orcid.org/0000-0002-7145-2544, Reisser, A., Rosenwald, A., Schwarz, K. ORCID: https://orcid.org/0000-0003-3178-5990, Sundararaj, S., Weilemann, A. ORCID: https://orcid.org/0009-0001-1340-6486, Winkler, W. ORCID: https://orcid.org/0000-0001-8807-9259, Xu, W., Lenz, G. ORCID: https://orcid.org/0000-0002-4728-1693, Rajewsky, K. ORCID: https://orcid.org/0000-0002-6633-6370, Wasserman, W.W. ORCID: https://orcid.org/0000-0001-6098-6412, Cockerill, P.N. ORCID: https://orcid.org/0000-0002-4410-8174, Scheidereit, C. ORCID: https://orcid.org/0000-0002-0446-6129, Siebert, R., Küppers, R., Grosschedl, R. ORCID: https://orcid.org/0000-0002-0058-1250, Janz, M. ORCID: https://orcid.org/0000-0002-1127-0044, Bonifer, C. ORCID: https://orcid.org/0000-0002-4267-0825 and Mathas, S. ORCID: https://orcid.org/0000-0001-9626-1413
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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. |
| Keywords: | B-Lymphocytes, DNA, Gene Expression Regulation, Interferon Regulatory Factors, Lymphoma |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 14 |
| Number: | 1 |
| Page Range: | 6947 |
| Date: | 7 November 2023 |
| Official Publication: | https://doi.org/10.1038/s41467-023-41954-8 |
| PubMed: | View item in PubMed |
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