Frequent ZNF217 mutations lead to transcriptional deregulation of interferon signal transduction via altered chromatin accessibility in B cell lymphoma

Briest, Franziska; Noerenberg, Daniel; Hennch, Cornelius; Yoshida, Kenichi; Hablesreiter, Raphael; Nimo, Jose; Sasca, Daniel; Kirchner, Marieluise; Mansouri, Larry; Inoue, Yoshikage; Wiegand, Laura; Staiger, Annette M.; Casadei, Beatrice; Korkolopoulou, Penelope; Weiner, January; Lopez-Guillermo, Armando; Warth, Arne; Schneider, Tamás; Nagy, Ákos; Klapper, Wolfram; Hummel, Michael; Kanellis, George; Anagnostopoulos, Ioannis; Mertins, Philipp; Bullinger, Lars; Rosenquist, Richard; Vassilakopoulos, Theodoros P.; Ott, German; Ogawa, Seishi; Damm, Frederik

doi:10.1038/s41375-023-02013-9

Cited by 4 publications

(4 citation statements)

References 60 publications

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“…The 10 most frequently mutated genes included SOCS1 (86%) , B2M (67%) , ITPKB (64%) , ACTB (58%) , STAT6 (58%) , IGLL5 (56%) , TNFAIP3 (53%) , NFKBIE (49%) , GNA13 (47%), and ZNF217 (36%). An exome-wide comparison between cHL and DLBCL identified mutated genes that seem to be particularly enriched in PMBCL, such as ZNF217 , 31 CD58 , and DUSP2 4,5,43-49 (Data Supplement, Fig S3).…”

Section: Resultsmentioning

confidence: 99%

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Genetic Characterization of Primary Mediastinal B-Cell Lymphoma: Pathogenesis and Patient Outcomes

Noerenberg,

Briest,

Hennch

et al. 2024

JCO

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PURPOSE Primary mediastinal large B-cell lymphoma (PMBCL) is a rare aggressive lymphoma predominantly affecting young female patients. Large-scale genomic investigations and genetic markers for risk stratification are lacking. PATIENTS AND METHODS To elucidate the full spectrum of genomic alterations, samples from 340 patients with previously untreated PMBCL were investigated by whole-genome (n = 20), whole-exome (n = 78), and targeted (n = 308) sequencing. Statistically significant prognostic variables were identified using a multivariable Cox regression model and confirmed by L1/L2 regularized regressions. RESULTS Whole-genome sequencing revealed a commonly disrupted p53 pathway with nonredundant somatic structural variations (SVs) in TP53-related genes ( TP63, TP73, and WWOX) and identified novel SVs facilitating immune evasion ( DOCK8 and CD83). Integration of mutation and copy-number data expanded the repertoire of known PMBCL alterations (eg, ARID1A, P2RY8, and PLXNC1) with a previously unrecognized role for epigenetic/chromatin modifiers. Multivariable analysis identified six genetic lesions with significant prognostic impact. CD58 mutations (31%) showed the strongest association with worse PFS (hazard ratio [HR], 2.52 [95% CI, 1.50 to 4.21]; P < .001) and overall survival (HR, 2.33 [95% CI, 1.14 to 4.76]; P = .02). IPI high-risk patients with mutated CD58 demonstrated a particularly poor prognosis, with 5-year PFS and OS rates of 41% and 58%, respectively. The adverse prognostic significance of the CD58 mutation status was predominantly observed in patients treated with nonintensified regimens, indicating that dose intensification may, to some extent, mitigate the impact of this high-risk marker. By contrast, DUSP2-mutated patients (24%) displayed durable responses (PFS: HR, 0.2 [95% CI, 0.07 to 0.55]; P = .002) and prolonged OS (HR, 0.11 [95% CI, 0.01 to 0.78]; P = .028). Upon CHOP-like treatment, these patients had very favorable outcome, with 5-year PFS and OS rates of 93% and 98%, respectively. CONCLUSION This large-scale genomic characterization of PMBCL identified novel treatment targets and genetic lesions for refined risk stratification. DUSP2 and CD58 mutation analyses may guide treatment decisions between rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab.

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Section: Resultsmentioning

confidence: 99%

“…A customdesigned targeted sequencing panel covering 106 genes was based on previous exploratory analysis and literature review. [4][5][6]15,31 Additional details on library preparations and specifics of SV, SCNA, and somatic variant calling are provided in the Data Supplement. 32…”

Section: Genomic Data Analysismentioning

confidence: 99%

Genetic Characterization of Primary Mediastinal B-Cell Lymphoma: Pathogenesis and Patient Outcomes

Noerenberg,

Briest,

Hennch

et al. 2024

JCO

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“…A detailed description of the PMBCL patient cohort, applied sequencing workflow, and corresponding bioinformatical analysis are described in ref. 72…”

Section: Irf4 Mutation Analysis In Pmbcl Patientsmentioning

confidence: 99%

“…RNA-Seq data of mouse splenic B cells are deposited in ArrayExpress database under ID E-MTAB-12522. High-througput sequencing data of the PMBCL cohort is in part publicly available 72…”

Section: Reporting Summarymentioning

confidence: 99%

Transcriptional reprogramming by mutated IRF4 in lymphoma

Schleussner,

Cauchy,

Franke

et al. 2023

Nat Commun

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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.

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