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


  • 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


  • Leukemia


  • Leukemia 37 (11): 2237-2249


  • 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.