Mutations in chromatin regulators are widespread in cancer. Among them, the histone H3 lysine 27 methyltransferase Polycomb Repressive Complex 2 (PRC2) shows distinct alterations according to tumor type. This specificity is poorly understood. Here, we model several PRC2 alterations in one isogenic system to reveal their comparative effects. Focusing then on lymphoma-associated EZH2 mutations, we show that Ezh2^Y641F induces aberrant H3K27 methylation patterns even without wild-type Ezh2, which are alleviated by partial PRC2 inhibition. Remarkably, Ezh2^Y641F rewires the response to PRC2 inhibition, leading to induction of antigen presentation genes. Using a unique longitudinal follicular lymphoma cohort, we further link EZH2 status to abnormal H3K27 methylation. We also uncover unexpected variability in the mutational landscape of successive biopsies, pointing to frequent co-existence of different clones and cautioning against stratifying patients based on single sampling. Our results clarify how oncogenic PRC2 mutations disrupt chromatin and transcription, and the therapeutic vulnerabilities this creates.

染色质调节因子的突变在癌症中广泛存在。其中，组蛋白 H3 赖氨酸 27 甲基转移酶多梳抑制复合物 2 (PRC2) 根据肿瘤类型显示出明显的变化。人们对这种特殊性知之甚少。在这里，我们对一个同基因系统中的多个 PRC2 改变进行建模，以揭示它们的比较效果。然后关注淋巴瘤相关的EZH2突变，我们发现即使没有野生型Ezh2 ， Ezh2 ^Y641F也会诱导异常的 H3K27 甲基化模式，部分 PRC2 抑制可以缓解这种情况。值得注意的是，Ezh2 ^Y641F重新连接了对 PRC2 抑制的反应，导致抗原呈递基因的诱导。使用独特的纵向滤泡性淋巴瘤队列，我们​​进一步将EZH2状态与异常 H3K27 甲基化联系起来。我们还发现了连续活检的突变情况中意想不到的变化，指出不同克隆的频繁共存，并警告不要根据单次采样对患者进行分层。我们的结果阐明了致癌性 PRC2 突变如何破坏染色质和转录，以及由此产生的治疗漏洞。