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. Profiling the resistance landscape to PRC2 inhibitors in EZH2-mutant lymphoma with CRISPR-suppressor scanning reveals drug addiction mutations and a repressive methylation ceiling. Surpassing the ceiling with SETD2 inhibition halts lymphoma growth.