EZH2-driven immune evasion defines high-risk pediatric AML with t(16;21) FUS::ERG gene fusion

Buteyn NJ, Burke CG, Sartori VJ, Deering-Gardner E, DeBruine ZJ, Kamarudin D, Chandler DP, Monovich AC, Perez MW, Yi JS, Ries RE, Alonzo TA, Ryan RJ, Meshinchi S, Triche TJ Jr. EZH2-driven immune evasion defines high-risk pediatric AML with t(16;21) FUS::ERG gene fusion. bioRxiv. 2024 Jun 25;. doi: 10.1101/2024.05.14.594150. PubMed PMID: 38798454; PubMed Central PMCID: PMC11118270.

The past 25 years of clinical trials have produced few improvements in pediatric AML (pAML) outcomes. This is acutely evident in patients with t(16;21)(p11;q22), yielding FUS::ERG. Patients with FUS::ERG-positive AML relapse quickly and do not respond to transplantation. Major histocompatibility complex (MHC) class I & II receptors and costimulatory molecules are absent at diagnosis in FUS::ERG-positive AML, mirroring the phenotype and outcomes of post-transplant relapse. We show that this is driven by overexpression of EZH2, in vitro and in multiple clinical cohorts. While FUS::ERG AML is the most extreme example, this phenotype is shared by lethal CBFA2T3::GLIS2-driven AML, and patients with RUNX1::RUNX1T1 have significantly worse outcomes when EZH2 overexpression co-occurs. The FDA-approved EZH2 inhibitor tazemetostat reverses this phenotype, re-establishes MHC presentation, and elicits immune effector cell-mediated elimination. EZH2 inhibitors may provide the first targeted therapeutic frontline option for AML patients with FUS::ERG, with the potential for broader frontline immunostimulatory benefits.