EZH2 mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition

Pierre Romero, Laia Richart, Setareh Aflaki, Ambre Petitalot, Megan Burton, Audrey Michaud, Julien Masliah-Planchon, Frédérique Kuhnowski, Samuel Le Cam, Carlos Baliñas-Gavira, Céline Méaudre, Armelle Luscan, Abderaouf Hamza, Patricia Legoix, Anne Vincent-Salomon, Michel Wassef, Daniel Holoch () and Raphaël Margueron ()
Additional contact information
Pierre Romero: Sorbonne University
Laia Richart: Sorbonne University
Setareh Aflaki: Sorbonne University
Ambre Petitalot: Sorbonne University
Megan Burton: Sorbonne University
Audrey Michaud: Sorbonne University
Julien Masliah-Planchon: Paris Sciences et Lettres Research University
Frédérique Kuhnowski: Paris Sciences et Lettres Research University
Samuel Le Cam: Sorbonne University
Carlos Baliñas-Gavira: Sorbonne University
Céline Méaudre: Paris Sciences et Lettres Research University
Armelle Luscan: Sorbonne University
Abderaouf Hamza: Paris Sciences et Lettres Research University
Patricia Legoix: Paris Sciences et Lettres Research University
Anne Vincent-Salomon: Paris Sciences et Lettres Research University
Michel Wassef: Sorbonne University
Daniel Holoch: Sorbonne University
Raphaël Margueron: Sorbonne University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Mutations in chromatin regulators are widespread in cancer. Among them, the histone H3 lysine 27 methyltransferase Polycomb Repressive Complex 2 (PRC2) shows distinct alterations according to tumor type. This specificity is poorly understood. Here, we model several PRC2 alterations in one isogenic system to reveal their comparative effects. Focusing then on lymphoma-associated EZH2 mutations, we show that Ezh2Y641F induces aberrant H3K27 methylation patterns even without wild-type Ezh2, which are alleviated by partial PRC2 inhibition. Remarkably, Ezh2Y641F rewires the response to PRC2 inhibition, leading to induction of antigen presentation genes. Using a unique longitudinal follicular lymphoma cohort, we further link EZH2 status to abnormal H3K27 methylation. We also uncover unexpected variability in the mutational landscape of successive biopsies, pointing to frequent co-existence of different clones and cautioning against stratifying patients based on single sampling. Our results clarify how oncogenic PRC2 mutations disrupt chromatin and transcription, and the therapeutic vulnerabilities this creates.

Date: 2024
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DOI: 10.1038/s41467-024-47701-x

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