Enhancer reprogramming in PRC2-deficient malignant peripheral nerve sheath tumors induces a targetable de-differentiated state

Acta Neuropathol. 2021 Sep;142(3):565-590. doi: 10.1007/s00401-021-02341-z. Epub 2021 Jul 20.


Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that frequently harbor genetic alterations in polycomb repressor complex 2 (PRC2) components-SUZ12 and EED. Here, we show that PRC2 loss confers a dedifferentiated early neural-crest phenotype which is exclusive to PRC2-mutant MPNSTs and not a feature of neurofibromas. Neural crest phenotype in PRC2 mutant MPNSTs was validated via cross-species comparative analysis using spontaneous and transgenic MPNST models. Systematic chromatin state profiling of the MPNST cells showed extensive epigenomic reprogramming or chromatin states associated with PRC2 loss and identified gains of active enhancer states/super-enhancers on early neural crest regulators in PRC2-mutant conditions around genomic loci that harbored repressed/poised states in PRC2-WT MPNST cells. Consistently, inverse correlation between H3K27me3 loss and H3K27Ac gain was noted in MPNSTs. Epigenetic editing experiments established functional roles for enhancer gains on DLX5-a key regulator of neural crest phenotype. Consistently, blockade of enhancer activity by bromodomain inhibitors specifically suppressed this neural crest phenotype and tumor burden in PRC2-mutant PDXs. Together, these findings reveal accumulation of dedifferentiated neural crest like state in PRC2-mutant MPNSTs that can be targeted by enhancer blockade.

Keywords: BRD4 inhibitor; Enhancer activation; Epigenomic reprogramming; Malignant peripheral nerve sheath tumor; Neural-crest phenotype; Polycomb repressor complex 2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biomarkers, Tumor
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Dogs
  • Enhancer Elements, Genetic / genetics
  • Epigenesis, Genetic / genetics
  • Homeodomain Proteins / genetics
  • Humans
  • Mice
  • Mice, Transgenic
  • Mutation
  • Nerve Sheath Neoplasms / drug therapy*
  • Nerve Sheath Neoplasms / genetics*
  • Nerve Sheath Neoplasms / pathology
  • Neural Crest / pathology
  • Peripheral Nervous System Neoplasms / drug therapy*
  • Peripheral Nervous System Neoplasms / genetics*
  • Peripheral Nervous System Neoplasms / pathology
  • Polycomb Repressive Complex 2 / genetics*
  • Species Specificity
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Xenograft Model Antitumor Assays
  • Zebrafish


  • BRD4 protein, human
  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • DLX5 protein, human
  • Homeodomain Proteins
  • Transcription Factors
  • Polycomb Repressive Complex 2