Exploring the translational potential of EZH2-controlled fetal gene signature in AML

Enhancer of zeste homolog 2 (EZH2) is the main catalytic subunit of PRC2, guiding H3K27 tri-methylation and gene silencing. Mutations in EZH2 occur in 2–13% of AML patients. Our work showed that EZH2 loss reactivates fetal gene signatures, typically silent in adult cells but elevated during embryogenesis and tumorigenesis. Such reactivation, enriched in patients with EZH2 or PRC2 mutations, emerged as a leukemogenic driver in mouse models and was predominantly observed in high-risk AML patients. To probe these fetal gene signature we performed CRISPR-Cas9 screens to pinpoint reactivated fetal genes that function as therapeutically exploitable vulnerabilities. Additionally, we tested and optimized mutant Cas12a based CRISPR interference to complement the targeting of coding variants with fine mapping enhancers that regulate fetal gene expression. By illuminating the molecular mechanisms of EZH2 in driving fetal gene reactivation, our study will advance targeted therapeutic strategies for AML patients.

Publication History

Article published online:
09 May 2025