Journal
CANCER DISCOVERY
Volume 12, Issue 6, Pages 1449-1461Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-21-0980
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Funding
- Italian Ministry of Health [RF-2011-02351998, RF-2011-02348034, GR-2018-12367860]
- Associazione Italiana per la Ricerca sul Cancro [14162, 22197]
- Associazione Italiana per la Ricerca sul Cancro (My First AIRC Grant MFAG 2019) [23321]
- Telethon
- Career Development Award from Human Frontier Science Program
- European Hematology Association
- Leukemia Research Foundation
- Japan Agency for Medical Research and Development (AMED)
- New York Stem Cell Foundation
- San Raffaele Pilot Grant
- Interstellar Initiative on Healthy Longevity from the New York Academy of Sciences
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Immune escape is a major factor contributing to the relapse of AML after allo-HCT. In this study, PRC2 is identified as the key epigenetic driver of this immune escape modality. Inhibition of PRC2 can restore the expression of HLA class II molecules in AML relapse, providing a potential innovative approach for personalized epigenetic immunotherapies.
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 nongenomic 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 (PDX), we identify the polycomb repressive complex 2 (PRC2) as a 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. Pharmacologic 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. SIGNIFICANCE: Loss of HLA class II expression represents a frequent mechanism of leukemia post-transplantation relapse. Here we identify PRC2 as the main epigenetic driver of this immune escape modality and show that its chemical inhibition can reinstate a proficient graft-versus-leukemia effect, providing an innovative rationale for personalized epigenetic immunotherapies.
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