表观遗传学
染色质
PRC2
髓系白血病
DNA甲基化
生物
癌症研究
白血病
免疫系统
移植
人类白细胞抗原
免疫学
作者
VALENTINA GAMBACORTA,Stefano Beretta,Martina Ciccimarra,Laura Zito,Kety Giannetti,Angela Andrisani,Daniela Gnani,Lucia Zanotti,Giacomo Oliveira,Matteo Carrabba,Davide Cittaro,Ivan Merelli,Fabio Ciceri,Raffaella di Micco,Luca Vago
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2022-03-07
标识
DOI:10.1158/2159-8290.cd-21-0980
摘要
Abstract Immune escape represents a major driver of acute myeloid leukemia (AML) reemergence after allogeneic hematopoietic cell transplantation (allo-HCT), with up to 40% of relapses prompted by non-genomic loss of HLA class II expression in leukemia cells. By integrative analysis of gene expression, DNA methylation, and chromatin accessibility in paired diagnosis/relapse primary samples and in the respective patient-derived xenografts (PDXs), we identify the polycomb repressive complex 2 (PRC2) as key epigenetic driver of this immune escape modality. We report that loss of expression of HLA class II molecules is accompanied by a PRC2-dependent reduction in chromatin accessibility. Pharmacological inhibition of PRC2 subunits rescues HLA class II expression in AML relapses in vitro and in vivo, with consequent recovery of leukemia recognition by CD4+ T cells. Our results uncover a novel link between epigenetics and leukemia immune escape, which may rapidly translate into innovative strategies to cure or prevent AML post-transplantation relapse.
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