EZH2-driven immune evasion defines high-risk pediatric AML with t(16;21) FUS::ERG gene fusion.
bioRxiv
; 2024 Jun 25.
Article
em En
| MEDLINE
| ID: mdl-38798454
ABSTRACT
Despite decades of research, acute myeloid leukemia (AML) remains a remarkably lethal malignancy. While pediatric AML (pAML) carries a more favorable prognosis than adult AML, the past 25 years of large clinical trials have produced few improvements in pAML survival. Nowhere is this more evident than in patients carrying a t(16;21)(p11;q22) translocation, which yields the FUSERG fusion transcript. Patients with FUSERG-positive AML are often primary refractory, and most responders quickly relapse. In COG clinical trials, allogeneic stem cell transplantation was of no benefit to FUSERG pAML patients; 100% of transplanted patients succumbed to their disease. Expression of major histocompatibility complex (MHC) class I & II and costimulatory molecules is absent at diagnosis in FUSERG AML, mirroring the epigenetic mechanism of post-transplant relapse seen in adult AML and its associated dismal outcomes. Here we show that this class-defining immune-repressive phenotype is driven by overexpression of the EZH2 histone lysine methyltransferase in vitro and in multiple clinical cohorts. We show that treatment with the FDA-approved EZH2 inhibitor tazemetostat along with IFN-γ reverses this phenotype, re-establishes MHC presentation, and severely impairs the viability of FUSERG AML cells. EZH2 inhibitors may thus provide the first targeted therapeutic option for patients with this high-risk subtype of pAML, with particular benefit as a bridge to successful allogeneic stem cell transplantation.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
BioRxiv
Ano de publicação:
2024
Tipo de documento:
Article
País de publicação:
Estados Unidos