Integrated Multiomic Profiling Identifies the Epigenetic Regulator PRC2 as a Therapeutic Target to Counteract Leukemia Immune Escape and Relapse [ATAC-seq]

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. Overall design: Analysis of differential chromatin accessibility of 5 relapse post transplantation vs paired diagnostic samples and 5 relapse post chemotherapy vs paired diagnostic samples. 3 relapse post transplantation from PDXs were treated with EPZ-6438 and compared with DMSO controls.