Drug addiction unveils a repressive methylation ceiling in EZH2-mutant lymphoma

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.

Automated summary

Drug addiction in cancer cells reveals cell signaling mechanisms and dependencies. Mutations that confer drug addiction to inhibitors of the PRC2 transcriptional repressor are discovered in diffuse large B-cell lymphoma. Drug addiction is mediated by hypermorphic mutations in the CXC domain of the catalytic subunit EZH2, maintaining H3K27me3 levels even in the presence of inhibitors. Exploiting this vulnerability, inhibition of SETD2 induces the spread of H3K27me3 and blocks lymphoma growth. These findings demonstrate the role of chromatin landscapes in cancer cells and highlight the potential for discovering cancer vulnerabilities through drug addiction mutations.