Frequent ZNF217 mutations lead to transcriptional deregulation of interferon signal transduction via altered chromatin accessibility in B cell lymphoma
Authors
- F. Briest
- D. Noerenberg
- C. Hennch
- K. Yoshida
- R. Hablesreiter
- J. Nimo
- D. Sasca
- M. Kirchner
- L. Mansouri
- Y. Inoue
- L. Wiegand
- A.M. Staiger
- B. Casadei
- P. Korkolopoulou
- J. Weiner
- A. Lopez-Guillermo
- A. Warth
- T. Schneider
- Á. Nagy
- W. Klapper
- M. Hummel
- G. Kanellis
- I. Anagnostopoulos
- P. Mertins
- L. Bullinger
- R. Rosenquist
- T.P. Vassilakopoulos
- G. Ott
- S. Ogawa
- F. Damm
Journal
- Leukemia
Citation
- Leukemia 37 (11): 2237-2249
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.