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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: |
Briest, F.  ORCID: https://orcid.org/0000-0001-5969-9467, Noerenberg, D., Hennch, C. ORCID: https://orcid.org/0000-0003-4104-5531, Yoshida, K. ORCID: https://orcid.org/0000-0003-4612-2778, Hablesreiter, R. ORCID: https://orcid.org/0000-0002-4586-932X, Nimo, J. ORCID: https://orcid.org/0000-0002-1565-7799, Sasca, D. ORCID: https://orcid.org/0000-0003-0330-7959, Kirchner, M. ORCID: https://orcid.org/0000-0002-7049-534X, Mansouri, L., Inoue, Y., Wiegand, L. ORCID: https://orcid.org/0000-0002-9917-7396, Staiger, A.M. ORCID: https://orcid.org/0000-0002-5896-3200, Casadei, B., Korkolopoulou, P., Weiner, J. ORCID: https://orcid.org/0000-0003-1438-7819, Lopez-Guillermo, A., Warth, A., Schneider, T., Nagy, Á. ORCID: https://orcid.org/0000-0001-6118-0365, Klapper, W., Hummel, M. ORCID: https://orcid.org/0000-0001-6717-605X, Kanellis, G., Anagnostopoulos, I. ORCID: https://orcid.org/0000-0002-5043-6043, Mertins, P. ORCID: https://orcid.org/0000-0002-2245-528X, Bullinger, L. ORCID: https://orcid.org/0000-0002-5890-5510, Rosenquist, R. ORCID: https://orcid.org/0000-0002-0211-8788, Vassilakopoulos, T.P., Ott, G., Ogawa, S. ORCID: https://orcid.org/0000-0002-7778-5374 and Damm, F. ORCID: https://orcid.org/0000-0001-5553-1173
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| 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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