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

• DOI: 10.1016/j.celrep.2022.111363
• Publication Date: 2022-09-20T14:47:46Z
• Authors: Xiyuan Zhang; Hannah E. Lou; Vishaka Gopalan; Zhihui Liu; Hilda M. Jafarah; Haiyan Lei; Paige Jones; Carly M. Sayers; Marielle E. Yohe; Prashant Chittiboina; Brigitte C. Widemann; Carol J. Thiele; Michael C. Kelly; Sridhar Hannenhalli; Jack F. Shern
• Keywords: 0301 basic medicine; 03 medical and health sciences; Carcinogenesis; Neurofibrosarcoma; Interferon Regulatory Factors; Interferon Type I; Polycomb Repressive Complex 2; Humans; Article; Chromatin

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.