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| Item Type: | Article |
|---|---|
| Title: | Transcriptional reprogramming by mutated IRF4 in lymphoma |
| Creators Name: | 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., 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, W.W., Cockerill, P.N., Scheidereit, C., Siebert, R., Küppers, R., Grosschedl, R., Janz, M., Bonifer, C. and Mathas, S. |
| 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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