Integrated Multiomic Profiling Identifies the Epigenetic Regulator PRC2 as a Therapeutic Target to Counteract Leukemia Immune Escape and Relapse

被引:33
作者
Gambacorta, Valentina [1 ,2 ,3 ]
Beretta, Stefano [4 ,5 ]
Ciccimarra, Martina [1 ]
Zito, Laura [1 ]
Giannetti, Kety [2 ]
Andrisani, Angela [1 ]
Gnani, Daniela [2 ]
Zanotti, Lucia [1 ]
Oliveira, Giacomo [1 ]
Carrabba, Matteo Giovanni [6 ]
Cittaro, Davide [7 ]
Merelli, Ivan [4 ,5 ]
Ciceri, Fabio [6 ,8 ]
Di Micco, Raffaella [2 ]
Vago, Luca [1 ,6 ,8 ]
机构
[1] IRCCS San Raffaele Sci Inst, Div Immunol Transplantat & Infect Dis, Unit Immunogenet Leukemia Genom & Immunobiol, Milan, Italy
[2] IRCCS San Raffaele Sci Inst, San Raffaele Telethon Inst Gene Therapy SR TIGET, Unit Senescence Stem Cell Aging Differentiat & Ca, Via Olgettina 60, Milan, Italy
[3] Univ Milano Bicocca, Milan, Italy
[4] CNR, Inst Biomed Technol, Segrate, Italy
[5] IRCCS San Raffaele Sci Inst, San Raffaele Telethon Inst Gene Therapy SR TIGET, Milan, Italy
[6] IRCCS San Raffaele Sci Inst, Hematol & Bone Marrow Transplantat Unit, Milan, Italy
[7] IRCCS Osped San Raffaele COSR, IRCCS San Raffaele Sci Inst, Ctr Omics Sci, Milan, Italy
[8] San Raffaele Vita Salute Univ, Milan, Italy
关键词
MHC-II; CELL; HLA; ALIGNMENT; LYMPHOMA; DISEASE; MICE;
D O I
10.1158/2159-8290.CD-21-0980
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:1449 / 1461
页数:13
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