An analysis of 51 malignant peripheral nerve sheath tumours (MPNSTs) from patients with neurofibromatosis type I with and without mutations in NF1, has identified mutations in one of the components of the Polycomb repressive complex 2 (PRC2), SUZ12. Mutations in Suz12 and Nf1 cooperated to promote development of MPNSTs and gliomas in mice, and SUZ12 loss promoted an epigenetic switch from histone H3 lysine 37 trimethylation (H3K37me3) to H3K27 acetylation (H3K27ac), a transcriptional activating signal that recruits bromodomain proteins. SUZ12-mutant MPNSTs were sensitive to the bromodomain inhibitor JQ1. Treatment with JQ1 in combination with MEK inhibitors promoted tumour regression and suppressed RAS transcriptional output, suggesting that SUZ12 loss might be amplifying RAS-driven transcription.