Drug addiction, a phenomenon where cancer cells paradoxically depend on continuous drug treatment for survival, has uncovered cell signaling mechanisms and cancer codependencies. Here we discover mutations that confer drug addiction to inhibitors of the transcriptional repressor polycomb repressive complex 2 (PRC2) in diffuse large B-cell lymphoma. Drug addiction is mediated by hypermorphic mutations in the CXC domain of the catalytic subunit EZH2, which maintain H3K27me3 levels even in the presence of PRC2 inhibitors. Discontinuation of inhibitor treatment leads to overspreading of H3K27me3, surpassing a repressive methylation ceiling compatible with lymphoma cell survival. Exploiting this vulnerability, we show that inhibition of SETD2 similarly induces the spread of H3K27me3 and blocks lymphoma growth. Collectively, our findings demonstrate that constraints on chromatin landscapes can yield biphasic dependencies in epigenetic signaling in cancer cells. More broadly, we highlight how approaches to identify drug addiction mutations can be leveraged to discover cancer vulnerabilities.

药物成瘾是一种癌细胞矛盾地依赖持续药物治疗才能生存的现象，它揭示了细胞信号传导机制和癌症的相互依赖性。在这里，我们发现了弥漫性大 B 细胞淋巴瘤中转录抑制因子多梳抑制复合物 2 (PRC2) 抑制剂的突变，这些突变会导致药物成瘾。药物成瘾是由催化亚基 EZH2 CXC 结构域的超态突变介导的，即使在 PRC2 抑制剂存在的情况下，该突变也能维持 H3K27me3 水平。停止抑制剂治疗会导致 H3K27me3 过度扩散，超过与淋巴瘤细胞存活相容的抑制性甲基化上限。利用这一漏洞，我们发现 SETD2 的抑制同样会诱导 H3K27me3 的扩散并阻止淋巴瘤的生长。总的来说，我们的研究结果表明，对染色质景观的限制可以在癌细胞的表观遗传信号中产生双相依赖性。更广泛地说，我们强调如何利用识别毒瘾突变的方法来发现癌症的脆弱性。