RT Journal Article SR Electronic T1 Drug addiction mutations unveil a methylation ceiling in EZH2-mutant lymphoma JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.04.04.486977 DO 10.1101/2022.04.04.486977 A1 Hui Si Kwok A1 Allyson M. Freedy A1 Allison P. Siegenfeld A1 Julia W. Morriss A1 Amanda L. Waterbury A1 Stephen M. Kissler A1 Brian B. Liau YR 2022 UL http://biorxiv.org/content/early/2022/04/05/2022.04.04.486977.abstract AB Cancer mutations in Polycomb Repressive Complex 2 (PRC2) drive aberrant epigenetic states. Although therapies inhibiting the PRC2 enzymatic component EZH2 are FDA-approved, oncogene-specific dependencies remain to be discovered. Here, we identify mutations that confer both resistance and drug addiction to PRC2 inhibitors in EZH2-mutant lymphoma, resulting in cancer cells that paradoxically depend on drug for survival. Drug addiction is mediated by hypermorphic mutations in the CXC domain of EZH2, which maintain H3K27me3 levels even in the presence of PRC2 inhibitors. Drug removal leads to overspreading of H3K27me3, surpassing a repressive methylation ceiling compatible with lymphoma cell survival. Activating EZH2 cancer mutations establish an epigenetic state precariously close to this ceiling, which we show can be breached by inhibition of SETD2, a PRC2 antagonist, to block lymphoma growth. More broadly, we highlight how approaches to identify drug addiction mutations can be leveraged to discover cancer vulnerabilities.Competing Interest StatementBrian Liau is on the Scientific Advisory Board of H3 Biomedicine.