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.

恶性周围神经鞘瘤 (MPNST) 是一种软组织肉瘤，多梳阻遏复合物 2 (PRC2) 成分——SUZ12和EED经常出现遗传改变. 在这里，我们表明 PRC2 缺失赋予去分化的早期神经嵴表型，这是 PRC2 突变体 MPNST 独有的，而不是神经纤维瘤的特征。使用自发和转基因 MPNST 模型通过跨物种比较分析验证了 PRC2 突变体 MPNST 中的神经嵴表型。MPNST 细胞的系统染色质状态分析显示广泛的表观基因组重编程或与 PRC2 丢失相关的染色质状态，并确定了 PRC2 中早期神经嵴调节器的活性增强子状态/超级增强子的增益 - 基因组位点周围的突变条件在PRC2-WT MPNST 细胞。一贯地，在 MPNST 中注意到 H3K27me3 损失和 H3K27Ac 增益之间的负相关。表观遗传编辑实验确定了增强子对 DLX5 增益的功能作用——DLX5 是神经嵴表型的关键调节因子。一致地，溴结构域抑制剂对增强子活性的阻断特异性抑制了 PRC2 突变体 PDX 中的这种神经嵴表型和肿瘤负荷。总之，这些发现揭示了 PRC2 突变体 MPNST 中去分化神经嵴样状态的积累，可以通过增强子阻断作为目标。