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Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers [methylation]

ABSTRACT: Epigenetic therapy is emerging as a potential therapy for solid tumors. To investigate its mechanism of action, we performed integrative expression and methylation analysis of 63 cancer cell lines (breast, colorectal, and ovarian) after treatment with the DNA methyltransferase inhibitor 5-azacitidine (AZA). Gene Set Enrichment Analysis demonstrated significant enrichment for immunomodulatory pathways in all three cancers (14.4-31.3%) including interferon signaling, antigen processing and presentation, and cytokines/chemokines. Strong upregulation of cancer testis antigens was also observed. An AZA IMmune gene set (AIMs) derived from the union of these immunomodulatory pathway genes classified primary tumors from all three types, into “high” and “low” AIM gene expression subsets in tumor expression data from both TCGA and GEO (GSE42284, GSE10893, and GSE26712 for the colon, breast, and ovarian samples, respectively). Samples from selected patient biopsies showed upregulation of AIM genes after treatment with epigenetic therapy. These results point to a broad immune stimulatory role for DNA demethylating drugs in multiple cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57342 | GEO | 2014/05/08

SECONDARY ACCESSION(S): PRJNA246413

REPOSITORIES: GEO

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Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers [methylation]

Project description:Epigenetic therapy is emerging as a potential therapy for solid tumors. To investigate its mechanism of action, we performed integrative expression and methylation analysis of 63 cancer cell lines (breast, colorectal, and ovarian) after treatment with the DNA methyltransferase inhibitor 5-azacitidine (AZA). Gene Set Enrichment Analysis demonstrated significant enrichment for immunomodulatory pathways in all three cancers (14.4-31.3%) including interferon signaling, antigen processing and presentation, and cytokines/chemokines. Strong upregulation of cancer testis antigens was also observed. An AZA IMmune gene set (AIMs) derived from the union of these immunomodulatory pathway genes classified primary tumors from all three types, into “high” and “low” AIM gene expression subsets in tumor expression data from both TCGA and GEO (GSE42284, GSE10893, and GSE26712 for the colon, breast, and ovarian samples, respectively). Samples from selected patient biopsies showed upregulation of AIM genes after treatment with epigenetic therapy. These results point to a broad immune stimulatory role for DNA demethylating drugs in multiple cancers. A total of 338 samples were analyzed.

2014-05-08 | E-GEOD-57342 | biostudies-arrayexpress

Effect of AZA on gene expression of multiple breast, colon, and ovarian cell lines [expression]

Project description:Epigenetic therapy is emerging as a potential therapy for solid tumors. To investigate its mechanism of action, we performed integrative expression and methylation analysis of 63 cancer cell lines (breast, colorectal, and ovarian) after treatment with the DNA methyltransferase inhibitor 5-azacitidine (AZA). Gene Set Enrichment Analysis demonstrated significant enrichment for immunomodulatory pathways in all three cancers (14.4-31.3%) including interferon signaling, antigen processing and presentation, and cytokines/chemokines. Strong upregulation of cancer testis antigens was also observed. An AZA IMmune gene set (AIMs) derived from the union of these immunomodulatory pathway genes classified primary tumors from all three types, into M-bM-^@M-^\highM-bM-^@M-^] and M-bM-^@M-^\lowM-bM-^@M-^] AIM gene expression subsets in tumor expression data from both TCGA and GEO (GSE42284, GSE10893, and GSE26712 for the colon, breast, and ovarian samples, respectively). Samples from selected patient biopsies showed upregulation of AIM genes after treatment with epigenetic therapy. These results point to a broad immune stimulatory role for DNA demethylating drugs in multiple cancers. control vs. 5'-azacitidine-treated breast, colon, and ovarian cells at different time points (1, 3, 7, 10, 14, 21, or 28 days)

2014-05-08 | E-GEOD-57341 | biostudies-arrayexpress

Effect of AZA on gene expression of multiple breast, colon, and ovarian cell lines [expression]

2014-05-08 | GSE57341 | GEO

Identification of genes that may predict response to azacitidine treatment.

Project description:Azacitidine (AZA) is a hypomethylating drug used to treat disorders associated with myelodysplasia and related neoplasms. Approximately 50% of patients do not respond to AZA and have very poor outcomes. It is of great interest to identify predictive biomarkers for AZA responsiveness. Therefore, we searched for specific genes whose expression level was associated with response status.Using microarrays, we analyzed gene expression patterns in bone marrow CD34+ cells from 32 patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia with myelodysplasia-related changes before AZA therapy. Total RNA was isolated from bone marrow CD34+ cells obtained from myelodysplasia and related neoplasms patients who underwent treatment with 5-azacytidine (AZA, Vidaza). Using Illumina Human HT-12 v. 4 microarrays, we assayed gene expression profiles in patient CD34+ cells before AZA treatment in order to collect basic data for search for markers of the prediction of therapy response.

2016-02-10 | E-GEOD-77750 | biostudies-arrayexpress

Identification of genes that may predict response to azacitidine treatment.

2016-02-10 | GSE77750 | GEO

Inhibition of CBP synergizes with the RNA-dependent mechanisms of azacitidine by limiting protein translation

Project description:The nucleotide analogue azacitidine (AZA) interferes with RNA and DNA metabolism and is currently the best treatment option for a subset of patients with high-risk myelodysplastic syndromes. However, only half of treated patients respond and almost all patients that initially respond eventually relapse. Thus, response-predicting biomarkers and new treatment options are urgently needed to improve the clinical management of these patients. Here, we performed a loss-of-function shRNA screen in combination with AZA treatment in a MDS-derived AML cell line to identify chromatin regulators affecting drug response. We identified the histone acetyl transferase and transcriptional co-activator CBP as a major regulator of AZA sensitivity. Compounds inhibiting the enzymatic activity of CBP synergistically reduced viability of MDS-derived AML cell lines when combined with AZA. Surprisingly, this affect was specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is limited to DNA incorporation. The identification of immediate target genes suggested that the effect of CBP inhibition is mediated by downregulation of genes encoding the translational machinery, which could be confirmed in proteomic analysis of nascent proteins. Furthermore, proteins most affected by CBP inhibition include key drivers of cycle progression. Taken together, our results identify a novel synergistic interaction between CBP inhibitors and specifically AZA that warrants further evaluation for the combinatorial treatment of high-risk MDS patients. Beyond the scope of MDS and AZA, we provide novel insight in the function of clinically promising CBP inhibitors that is related to unexpected interference with the translational machinery.

2021-09-22 | PXD021738 | Pride

Azacitidine Modulates the Mesenchymal Stromal Cell Compartment in Myelodysplastic Syndromes

Project description:Mesenchymal stromal cells (MSC) are crucial components of the bone marrow (BM) microenvironment essential for regulating self-renewal, survival and differentiation of hematopoietic stem/progenitor cells (HSPC) in the stem cell niche. MSC are functionally and phenotypically altered in myelodysplastic syndromes (MDS), contributing to disease progression. MDS MSC do not harbor recurrent genetic alterations but have been shown to exhibit an altered methylome compared to MSC from healthy controls. We examined growth, differentiation and HSPC-supporting capacity of ex vivo expanded MSC from MDS patients in comparison to age-matched healthy controls after direct treatment in vitro with the hypomethylating agent azacitidine (AZA). We show that AZA exerts a direct effect on MSC by modulating their differentiation potential. Osteogenesis was significantly boosted in healthy MSC while adipogenesis was inhibited in both healthy and MDS MSC. In co-culture experiments, both AZA treated MDS MSC and healthy MSC exhibited enhanced support of non-clonal HSPC which was associated with increased cell cycle induction. Conversely, clonal MDS HSPC were inhibited by contact with AZA treated MSC. RNA-sequencing analyses of stromal cells revealed changes in pathways essential for HSPC support as well as in immune regulatory pathways. In sum, our data demonstrate that AZA treatment of stromal cells leads to upregulation of HSPC-supportive genes and cell cycle induction in co-cultured healthy HSPC, resulting in a proliferative advantage over clonal HSPC. Thus, restoration of functional hematopoiesis by AZA may be driven by activated stromal support factors in MSC providing cell cycle cues to healthy HSPC.

2018-12-19 | GSE112461 | GEO

Cellular Composition and 5hmC Signature Predict the Treatment Response of AML Patients to Azacitidine Combined with Chemotherapy

Project description:Azacitidine (AZA) is a DNA methyltransferase inhibitor and epigenetic modulator that can be an effective agent in combination with chemotherapy for patients with high-risk acute myeloid leukemia (AML). However, biological factors driving the therapeutic response of such hypomethylating agent (HMA)-based therapies remain unknown. Herein, the transcriptome and/or genome-wide 5-hydroxymethylcytosine (5hmC) are characterized for 41 patients with high-risk AML from a phase 1 clinical trial treated with AZA epigenetic priming followed by high-dose cytarabine and mitoxantrone (AZA-HiDAC-Mito). Digital cytometry reveals that responders have elevated Granulocyte-macrophage-progenitor-like (GMP-like) malignant cells displaying an active cell cycle program. Moreover, the enrichment of Natural killer (NK) cells predicts favorable outcome in patients receiving AZA-HiDAC-Mito therapy or other AZA-based therapies. Comparing 5hmC profiles before and after five-day treatment of AZA shows that AZA exposure induces dose-dependent 5hmC changes, the magnitude of which predicts overall survival (p=0.015). An XGBoost machine learning model is developed to predict the treatment response based on 5hmC levels of only 11 genes, achieving an area under the curve (AUC) of 0.860. These results suggest that cellular composition markedly impacts the treatment response, and showcase the prospect of 5hmC signature in predicting the outcomes of HMA-based therapies in AML.

2023-05-25 | GSE152431 | GEO

FUS-ERG induces late-onset azacitidine resistance in AML cells

Project description:Stable Ba/F3 transfectants with FUS-ERG were repeatedly exposed with Aza in a clinical administration manner of 7-days treatment and 21-days interval to investigate Aza sensitivity. RNA-seq was performed when Aza susceptibility began to change and identified genes with altered expression or transcript variants.

2022-11-21 | GSE217967 | GEO

Expression data comparing azacitidine and decitabine in non-small cell lung cancer lines

Project description:Azacitidine (AZA) and decitabine (DAC) are cytidine azanucleoside analogs with clinical activity in myelodysplastic syndromes (MDS) and potential activity in solid tumors. To better understand the mechanism of action of these drugs, we examined the effects of AZA and DAC in a panel of non-small cell lung cancer (NSCLC) cell lines. Of 5 NSCLC lines tested in a cell viability assay, all were sensitive to AZA (EC50 of 1.8M-bM-^@M-^S10.5 M-BM-5M), while only H1299 cells were equally sensitive to DAC (EC50 of 5.1 M-BM-5M). In the relatively DAC-insensitive cell line A549, both AZA and DAC caused DNA methyltransferase I depletion and DNA hypomethylation; however, only AZA significantly induced markers of DNA damage and apoptosis, suggesting that mechanisms in addition to, or other than, DNA hypomethylation are important for AZA-induced cell death. Cell cycle analysis indicated that AZA induced an accumulation of cells in sub-G1 phase, whereas DAC mainly caused an increase of cells in G2/M. Gene expression analysis of AZA- and DAC-treated cells revealed strikingly different profiles, with many genes distinctly regulated by each drug. In summary, while both AZA and DAC caused DNA hypomethylation, distinct effects were demonstrated on regulation of gene expression, cell cycle, DNA damage, and apoptosis. A549 and H1299 cells were treated with a dose range (0.3M-bM-^@M-^S3.0 M-NM-<M) of AZA or DAC for 48 hours, and effects on gene expression were assessed by microarray analysis.

2011-05-05 | E-GEOD-29077 | biostudies-arrayexpress

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