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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197417 | GEO | 2022/02/28

REPOSITORIES: GEO

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

Project description: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.

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

Project description: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 posttransplantation relapse.SignificanceLoss of HLA class II expression represents a frequent mechanism of leukemia posttransplantation 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. See related commentary by Köhler and Zeiser, p. 1410. This article is highlighted in the In This Issue feature, p. 1397.

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Full-length HLA class II sequences

Project description:Full-length HLA class II sequences

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Project description:HLA class II full-length submissions

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HLA Class I/II submissions 240607

Project description:HLA class I/II submissions 240607

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Chronic HIV-1 Tat action induces HLA-DR downregulation in B cells: a mechanism for lymphoma immune escape in people living with HIV

Project description:Despite the introduction of combined antiretroviral therapy (cART), people living with HIV (PLWH) still have an increased risk of EBV-associated B cell malignancies. In the HIV setting, B cell physiology is altered by co-existence with HIV-infected cells and the chronic action of secreted viral proteins, e.g. HIV-1 Tat that, once released, efficiently penetrates non-infected cells. Here we modeled a chronic action of HIV-1 Tat on B cells by ectopically expressing Tat or its mutant version TatC22G deprived of transactivation activity in two EBV-immortalized lymphoblastoid B cell lines. RNA-sequencing analysis revealed that Tat regulated the expression of hundreds of genes, including downregulation of a subset of genes related to MHC class II. Tat-induced transcriptional downregulation of HLA-DRB1, HLA-DRB5 genes was accompanied by a decrease in HLA-DR surface expression; this effect could be reproduced by co-cultivating B cells with Tat-expressing T cells. Notably, HLA-DRB1 expression in B cells was also decreased in PLWH. Chronic Tat presence decreased the NF-ᴋB pathway activity; this downregulated NF-ᴋB-dependent transcriptional targets, including MHC class II genes. Tat-induced HLA-DR downregulation in B cells also impaired EBV-specific CD4+ T cell response, which could contribute to the escape from immune surveillance and eventually promote B cell lymphomagenesis.

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