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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.

2022-02-28 | GSE197418 | GEO

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

2022-02-28 | GSE197416 | GEO

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Project description:HLA class II full-length submissions

| PRJEB41853 | ENA

Full-length HLA class II sequences

Project description:Full-length HLA class II sequences

| PRJEB42469 | ENA

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.

2022-09-04 | GSE212499 | GEO

Gene expression analysis of molecules with known function in HLA class II antigen processing and presentation in hematopoietic and (cytokine pre-treated) non-hematopoietic cells.

Project description:Gene expression analysis of molecules with known function in HLA class II antigen processing and presentation. Various hematopoietic cell types and (cytokine pre-treated) non-hematopoietic cells that are targeted in Graft-versus-Leukemia reactivity and Graft-versus-Host Disease were collected. Expression was compared between the different hematopoietic and non-hematopoietic cell types for the Invariant chain, HLA-DMA, HLA-DMB, HLA-DOA and HLA-DOB genes. The data show that the Invariant chain, HLA-DMA, HLA-DMB and HLA-DOA genes are expressed in all or the majority of cell types with HLA class II surface expression, whereas expression of the HLA-DOB gene is restricted to professional antigen presenting B-cells and mature dendritic cells.

2012-06-19 | GSE38798 | GEO

Gene expression analysis of molecules with known function in HLA class II antigen processing and presentation in hematopoietic and (cytokine pre-treated) non-hematopoietic cells.

2012-06-18 | E-GEOD-38798 | biostudies-arrayexpress

Upregulation of HLA expression in primary Uveal Melanoma by infiltrating leukocytes

Project description:Uveal melanoma (UM) with an inflammatory phenotype, characterized by infiltrating leukocytes and increased human leukocyte antigen (HLA) expression, carry an increased risk of death due to metastases. These tumors shoud be ideal for T-cell based therapies, yet it is not clear why prognostically-infaust tumors have a high HLA expression. We set out to determine whether the level of HLA molecules in UM is associated with other genetic factors, HLA transcriptional regulators, or microenvironmental factors. 28 enucleated UM were used to study HLA class I and II expression, and several regulators of HLA by immunohistochemistry, PCR microarray, qPCR and chromosome SNP-array. Fresh tumor samples of eight primary UM and four metastases were compared to their corresponding xenograft in SCID mice, using a PCR microarray and SNP array. Increased expression levels of HLA class I and II showed no dosage effect of chromosome 6p, but, as expected, were associated with monosomy of chromosome 3. Increased HLA class I and II protein levels were positively associated with their gene expression and with raised levels of the peptide-loading gene TAP1, and HLA transcriptional regulators IRF1, IRF8, CIITA, and NLRC5, revealing a higher transcriptional activity in prognostically-bad tumors. Implantation of fresh human tumor samples into SCID mice led to a loss of infiltrating leukocytes, and to a decreased expression of HLA class I and II genes , and their regulators. Our data provides evidence for a proper functioning HLA regulatory system in UM, offering a target for T-cell based therapies. NB: Here we show the PCR microarray (Illumina array).

2016-08-07 | GSE84976 | GEO

Immune Escape after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients with Acute Myeloid Leukemia

Project description:Although allogeneic hematopoietic cell transplantation (allo-HCT) is curative for high-risk pediatric acute myeloid leukemia (AML), disease relapse remains the primary cause of post-transplant mortality. To identify pressures imposed by allo-HCT on AML cells that escape the graft-versus-leukemia effect, we evaluated immune signatures in bone marrow samples from four pediatric patients using a multimodal single-cell approach. Downregulation of MHC class II (MHC-II) expression observed at post-transplant relapse was most profound in progenitor-like blasts and was accompanied by correlative changes in transcriptional regulation. Dysfunction of activated NK cells and CD8+ T cell subsets at the time of relapse was evidenced by the loss of IFN-γ response, TNF-a signaling via NF-kB, and IL-2/STAT5 signaling. Clonotype analysis of post-transplant relapse samples revealed expansion of dysfunctional T cells and enrichment of T regulatory and T helper cells. Using novel computational methods, our results illustrate a diverse immune-related transcriptional signature in post-transplantation relapses not previously reported in pediatric AML.

2023-06-26 | GSE207104 | GEO

HLA Class II analysis of human pancreatic beta cells

Project description:We interrogated the transcriptome from bulk-sorted T1D donor β-cells as compared to non-diabetic donors. We found β-cells also expressed mRNA for HLA Class II and Class II antigen presentation pathway components, but not a macrophage marker.

2019-03-01 | GSE121863 | GEO

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