Single-cell sequencing reveals activation of core transcription factors in PRC2-deficient malignant peripheral nerve sheath tumor.

Loss-of-function mutations in the polycomb repressive complex 2 (PRC2) occur frequently in malignant peripheral nerve sheath tumor, an aggressive sarcoma that arises from NF1 -deficient Schwann cells. To define the oncogenic mechanisms underlying PRC2 loss, we use engineered cells that dynamically reassemble a competent PRC2 coupled with single-cell sequencing from clinical samples. We discover a two-pronged oncogenic process: first, PRC2 loss leads to remodeling of the bivalent chromatin and enhancer landscape, causing the upregulation of developmentally regulated transcription factors that enforce a transcriptional circuit serving as the cell's core vulnerability. Second, PRC2 loss reduces type I interferon signaling and antigen presentation as downstream consequences of hyperactivated Ras and its cross talk with STAT/IRF transcription factors. Mapping of the transcriptional program of these PRC2-deficient tumor cells onto a constructed developmental trajectory of normal Schwann cells reveals that changes induced by PRC2 loss enforce a cellular profile characteristic of a primitive mesenchymal neural crest stem cell. [Display omitted] • PRC2 loss activates bivalent genes via transcriptional recruitment of active enhancers • PRC2 loss activates core TFs required to sustain the MPNST oncogenic program • PRC2-null MPNSTs mimic Schwann cell progenitors and reduce antigen presentation • scRNA-seq reveals heterogeneity within the MPNST microenvironment Zhang et al. provide evidence that PRC2 loss activates cell-fate-determining transcription factors by recruiting active enhancers and dampens type I interferon signaling and antigen presentation through transcriptional cross talk with the hyperactivated Ras. These observations are supported by integrative analysis of single-cell sequencing of patient MPNST samples. [ABSTRACT FROM AUTHOR]