ArticleNature chemical biology2023
Drug addiction unveils a repressive methylation ceiling in EZH2-mutant lymphoma.
Article in Nature chemical biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 17 citations in OpenAlex.
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- Nanoscaled, Fully Automated Hydrogen/Deuterium Exchange for Analysis of Macromolecular Assemblies Reaching the MDa Scale.Molecular & cellular proteomics : MCP · 2026Article
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Epigenetic synthetic lethality as a cancer therapeutic strategy: synergy of experimental and computational approaches.Epigenomics · 2025Review
- Structure-guided design and development of cyclic peptide allosteric activators of Polycomb Repressive Complex 2.bioRxiv : the preprint server for biology · 2025Article
- EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma.Neuro-oncology · 2025Article
- The impact of cell states on heterochromatin dynamics.The Biochemical journal · 2024Review
- Context-defined cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma.Nature communications · 2023Article
- Base editor screens for in situ mutational scanning at scale.Molecular cell · 2023Review
- Activity-based CRISPR scanning uncovers allostery in DNA methylation maintenance machinery.eLife · 2023Article
- CRISPR-Suppressor Scanning for Systematic Discovery of Drug-Resistance Mutations.Current protocols · 2022Article
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7 authors at 2 institutions in 1 country.
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Abstract
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.
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