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| Item Type: | Article |
|---|---|
| Title: | Frequent ZNF217 mutations lead to transcriptional deregulation of interferon signal transduction via altered chromatin accessibility in B cell lymphoma |
| Creators Name: | Briest, F. and Noerenberg, D. and Hennch, C. and Yoshida, K. and Hablesreiter, R. and Nimo, J. and Sasca, D. and Kirchner, M. and Mansouri, L. and Inoue, Y. and Wiegand, L. and Staiger, A.M. and Casadei, B. and Korkolopoulou, P. and Weiner, J. and Lopez-Guillermo, A. and Warth, A. and Schneider, T. and Nagy, Á. and Klapper, W. and Hummel, M. and Kanellis, G. and Anagnostopoulos, I. and Mertins, P. and Bullinger, L. and Rosenquist, R. and Vassilakopoulos, T.P. and Ott, G. and Ogawa, S. and Damm, F. |
| Abstract: | Recent exome-wide studies discovered frequent somatic mutations in the epigenetic modifier ZNF217 in primary mediastinal B cell lymphoma (PMBCL) and related disorders. As functional consequences of ZNF217 alterations remain unknown, we comprehensively evaluated their impact in PMBCL. Targeted sequencing identified genetic lesions affecting ZNF217 in 33% of 157 PMBCL patients. Subsequent gene expression profiling (n = 120) revealed changes in cytokine and interferon signal transduction in ZNF217-aberrant PMBCL cases. In vitro, knockout of ZNF217 led to changes in chromatin accessibility interfering with binding motifs for crucial lymphoma-associated transcription factors. This led to disturbed expression of interferon-responsive and inflammation-associated genes, altered cell behavior, and aberrant differentiation. Mass spectrometry demonstrates that ZNF217 acts within a histone modifier complex containing LSD1, CoREST and HDAC and interferes with H3K4 methylation and H3K27 acetylation. Concluding, our data suggest non-catalytic activity of ZNF217, which directs histone modifier complex function and controls B cell differentiation-associated patterns of chromatin structure. |
| Keywords: | B-Cell Lymphoma, Chromatin, Histones, Interferons, Mutation, Signal Transduction, Trans-Activators, Tumor Cell Line |
| Source: | Leukemia |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Volume: | 37 |
| Number: | 11 |
| Page Range: | 2237-2249 |
| Date: | November 2023 |
| Official Publication: | https://doi.org/10.1038/s41375-023-02013-9 |
| PubMed: | View item in PubMed |
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