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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.

SUBMITTER: Schleussner N

PROVIDER: S-EPMC10630337 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Transcriptional reprogramming by mutated IRF4 in lymphoma.

Schleussner Nikolai N Cauchy Pierre P Franke Vedran V Giefing Maciej M Fornes Oriol O Vankadari Naveen N Assi Salam A SA Costanza Mariantonia M Weniger Marc A MA Akalin Altuna A Anagnostopoulos Ioannis I Bukur Thomas T Casarotto Marco G MG Damm Frederik F Daumke Oliver O Edginton-White Benjamin B Gebhardt J Christof M JCM Grau Michael M Grunwald Stephan S Hansmann Martin-Leo ML Hartmann Sylvia S Huber Lionel L Kärgel Eva E Lusatis Simone S Noerenberg Daniel D Obier Nadine N Pannicke Ulrich U Fischer Anja A Reisser Anja A Rosenwald Andreas A Schwarz Klaus K Sundararaj Srinivasan S Weilemann Andre A Winkler Wiebke W Xu Wendan W Lenz Georg G Rajewsky Klaus K Wasserman Wyeth W WW Cockerill Peter N PN Scheidereit Claus C Siebert Reiner R Küppers Ralf R Grosschedl Rudolf R Janz Martin M Bonifer Constanze C Mathas Stephan S

Nature communications 20231107 1

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) ...[more]

PMID: 37935654

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Project description:The MYC transcription factor regulates a vast number of genes and is implicated in many human malignancies. In some hematological malignancies, MYC is frequently subject to missense mutations that enhance its transformation activity. Here, we use a novel murine cell system to (i) characterize the transcriptional effects of progressively increasing MYC levels as normal primary B-cells transform to lymphoma cells and (ii) determine how this gene regulation program is modified by lymphoma-associated MYC mutations (T58A and T58I) that enhance its transformation activity. Unlike many previous studies, the cell system exploits primary B-cells that are transduced to allow regulated MYC expression under circumstances where apoptosis and senescence pathways are abrogated by the over-expression of the Bcl-xL and BMI1 proteins. In such cells, transition from a normal to a lymphoma phenotype is directly dependent on the MYC expression level, without a requirement for secondary events that are normally required during MYC-driven oncogenic transformation. A generalized linear model approach allowed an integrated analysis of RNA sequencing data to identify regulated genes in relation to both progressively increasing MYC level and wild type or mutant status. Using this design, a total of 7569 regulated genes were identified, of which the majority (n = 7263) were regulated in response to progressively increased levels of wild type MYC, while a smaller number of genes (n = 917) were differentially regulated, compared to wild type MYC, in T58A MYC- and/or T58I MYC-expressing cells. Unlike most genes that are similarly regulated by both wild type and mutant MYC genes, the set of 917 genes did not significantly overlap with known lipopolysaccharide regulated genes, which represent genes regulated by MYC in normal B cells. The genes that were differently regulated in cells expressing mutant MYC proteins were significantly enriched in DNA replication and G2 phase to mitosis transition genes. Thus, mutants affecting MYC proteins may augment quantitative oncogenic effects on the expression of normal MYC-target genes with qualitative oncogenic effects, by which sets of cell cycle genes are abnormally targeted by MYC as B cells transition into lymphoma cells. The T58A and T58I mutations augment MYC-driven transformation by distinct mechanisms.

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Transcriptional reprogramming by mutated IRF4 in lymphoma.

Publications

Transcriptional reprogramming by mutated IRF4 in lymphoma.

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