Transcriptional reprogramming by mutated IRF4 in lymphoma
Autor/innen
- N. Schleussner
- P. Cauchy
- V. Franke
- M. Giefing
- O. Fornes
- N. Vankadari
- S.A. Assi
- M. Costanza
- M.A. Weniger
- A. Akalin
- I. Anagnostopoulos
- T. Bukur
- M.G. Casarotto
- F. Damm
- O. Daumke
- B. Edginton-White
- J.C.M. Gebhardt
- M. Grau
- S. Grunwald
- M.L. Hansmann
- S. Hartmann
- L. Huber
- E. Kärgel
- S. Lusatis
- D. Noerenberg
- N. Obier
- U. Pannicke
- A. Fischer
- A. Reisser
- A. Rosenwald
- K. Schwarz
- S. Sundararaj
- A. Weilemann
- W. Winkler
- W. Xu
- G. Lenz
- K. Rajewsky
- W.W. Wasserman
- P.N. Cockerill
- C. Scheidereit
- R. Siebert
- R. Küppers
- R. Grosschedl
- M. Janz
- C. Bonifer
- S. Mathas
Journal
- Nature Communications
Quellenangabe
- Nat Commun 14 (1): 6947
Zusammenfassung
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.