Transcriptional reprogramming by mutated IRF4 in lymphoma

Schleussner, Nikolai; Cauchy, Pierre; Franke, Vedran; Giefing, Maciej; Fornes, Oriol; Vankadari, Naveen; Assi, Salam A.; Costanza, Mariantonia; Weniger, Marc A.; Akalin, Altuna; Anagnostopoulos, Ioannis; Bukur, Thomas; Casarotto, Marco G.; Damm, Frederik; Daumke, Oliver; Edginton-White, Benjamin; Gebhardt, J. Christof M.; Grau, Michael; Grunwald, Stephan; Hansmann, Martin-Leo; Hartmann, Sylvia; Huber, Lionel; Kärgel, Eva; Lusatis, Simone; Noerenberg, Daniel; Obier, Nadine; Pannicke, Ulrich; Fischer, Anja; Reisser, Anja; Rosenwald, Andreas; Schwarz, Klaus; Sundararaj, Srinivasan; Weilemann, Andre; Winkler, Wiebke; Xu, Wendan; Lenz, Georg; Rajewsky, Klaus; Wasserman, Wyeth W.; Cockerill, Peter N.; Scheidereit, Claus; Siebert, Reiner; Küppers, Ralf; Grosschedl, Rudolf; Janz, Martin; Bonifer, Constanze; Mathas, Stephan

doi:10.1038/s41467-023-41954-8

Cited by 4 publications

(2 citation statements)

References 117 publications

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“…A general theme might be that GOF mutations outside the DNA binding domain preferentially hyperactivate existing programs while mutations in DNA binding domains could yield the emergence of novel and unanticipated programs. The C99R mutation in the DNA binding domain of the Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells, redirects binding to different motifs and therefore fundamentally alters transcriptional output ( 61 ).…”

Section: Discussionmentioning

confidence: 99%

STAT5B SH2 variants disrupt mammary enhancers and the stability of genetic programs during pregnancy

Lee,

Liu,

Hennighausen

2024

Preprint

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During pregnancy, mammary tissue undergoes expansion and differentiation, leading to lactation, a process regulated by the hormone prolactin through the JAK2-STAT5 pathway. STAT5 activation is key to successful lactation making the mammary gland an ideal experimental system to investigate the impact of human missense mutations on mammary tissue homeostasis. Here, we investigated the effects of two human variants in the STAT5B SH2 domain, which convert tyrosine 665 to either phenylalanine (Y665F) or histidine (Y665H), both shown to activate STAT5B in cell culture. We ported these mutations into the mouse genome and found distinct and divergent functions. Homozygous Stat5bY665H mice failed to form functional mammary tissue, leading to lactation failure, with impaired alveolar development and greatly reduced expression of key differentiation genes. STAT5BY665H failed to recognize mammary enhancers and impeded STAT5A binding. In contrast, mice carrying the Stat5bY665F mutation exhibited abnormal precocious development, accompanied by an early activation of the mammary transcription program and the induction of otherwise silent genetic programs. Physiological adaptation was observed in Stat5bY665H mice as continued exposure to pregnancy hormones led to lactation. In summary, our findings highlight that human STAT5B variants can modulate their response to cytokines and thereby impact mammary homeostasis and lactation.

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Section: Discussionmentioning

confidence: 99%

STAT5B SH2 variants disrupt mammary enhancers and the stability of genetic programs during pregnancy

Lee,

Liu,

Hennighausen

2024

Preprint

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“…This reduced target site occupation and the shorter residence time and lower transcription activation potency of RBPJ-K/E at sites bound by both species should limit the repression and activation of associated genes, in addition to proposed cofactor sequestration 38 . Moreover, off-target binding of HT-RBPJ-K/E as revealed by ChIP-Seq might lead to a gain-of-function phenotype, similar to point mutations of IRF4 associated with autosomal dominant combined immunodeficiency 71,83 . Overall, our data predict de-repression and lower than normal Notch-activated transcription of numerous Notch target genes in AOS.…”

Section: Discussionmentioning

confidence: 99%

Effectivein vivobinding energy landscape illustrates kinetic stability of RBPJ-DNA binding

Huynh,

Hoffmeister,

Friedrich

et al. 2023

Preprint

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Transcription factors such as RBPJ in Notch signal transduction bind to specific DNA sequences and initiate either repression or activation of genes. Which sites they select and how often and long they bind affects the efficiency of gene regulation. To resolve the underpinnings of RBPJ-DNA binding, we determined thein vivobinding free energy landscape of RBPJ using live-cell single-molecule tracking and genome-wide chromatin immunoprecipitation. Importantly, DNA binding of RBPJ was thermodynamically unstablein vivoand instead governed by the binding kinetics: Cofactors contributed to target site specificity by tuning both association and dissociation of unspecific binding, while mutation K195E underlying Adams-Oliver-Syndrome destabilized specific DNA binding by mainly altering the association rate. We showed thermodynamic instabilityin vivoalso for other transcription factors, indicating that kinetic rather than thermodynamic control of DNA binding might be a general feature of transcription factorsin vivo.

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Multi-omics analysis and response prediction of PD-1 monoclonal antibody containing regimens in patients with relapsed/refractory diffuse large B-cell lymphoma

Chen,

Qin,

Xue

et al. 2024

Cancer Immunol Immunother

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Patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) show varied responses to PD-1 monoclonal antibody (mAb) containing regimens. The mechanisms and predictive biomarkers for the efficacy of this regimen are unclear. This study retrospectively collected r/r DLBCL patients who received PD-1 mAb and rituximab regimens as salvage therapy. Clinical and genomic features were collected, and mechanisms were explored by multiplex immunofluorescence and digital spatial profiling. An artificial neural network (ANN) model was constructed to predict the response. Between October 16th, 2018 and May 4th, 2023, 50 r/r DLBCL patients were collected, 29 were response patients and 21 were non-response patients. CREBBP ( p = 0.029) and TP53 ( p = 0.015) alterations were statistically higher in non-response patients. Patients with PD-L1 CPS ≥ 5 were correlated with a longer overall survival (OS) than those with PD-L1 CPS < 5 (median OS: not reached vs. 9.7 months, hazard ratio [HR]: 3.8, 95% confidence interval [CI] 0.64–22.44, p = 0.016). Immune-related pathways were activated in response patients. The proportion and spatial organization of tumor-infiltrating immune cells affect the response. PD-L1 CPS level, age, and alterations of TP53 , MYD88 , CREBBP , EP300 , GNA13 were used to build an ANN predictive model that showed high prediction efficiency (training set area under curve [AUC] of 0.97 and test set AUC of 0.94). The proportion and spatial distribution of tumor-infiltrating immune cells may be related to the function of immune-related pathways, thereby influencing the efficacy of PD-1 mAb containing regimens. The ANN predictive model showed potential value in predicting the responses of r/r DLBCL patients received PD-1 mAb and rituximab regimens. Supplementary Information The online version contains supplementary material available at 10.1007/s00262-024-03840-0.

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Transcriptional reprogramming by mutated IRF4 in lymphoma

Cited by 4 publications

References 117 publications

STAT5B SH2 variants disrupt mammary enhancers and the stability of genetic programs during pregnancy

STAT5B SH2 variants disrupt mammary enhancers and the stability of genetic programs during pregnancy

Effectivein vivobinding energy landscape illustrates kinetic stability of RBPJ-DNA binding

Multi-omics analysis and response prediction of PD-1 monoclonal antibody containing regimens in patients with relapsed/refractory diffuse large B-cell lymphoma

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