Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Azacitidine treated AML cells reveals highly variable cell surface proteome remodeling [Affymetrix]

ABSTRACT: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are diseases of abnormal hematopoietic differentiation with aberrant epigenetic alterations. Azacitidine (AZA) is a DNA methyltransferase inhibitor (DNMTi) widely used to treat MDS and AML, yet the impact of AZA on the cell surface proteome has not been defined. To identify potential therapeutic targets for use in combination with AZA in AML patients, we investigated the effects of AZA treatment on four AML cell lines representing different stages of differentiation. The effect of AZA treatment on these cell lines was characterized at three levels: the DNA methylome, the transcriptome, and the cell surface proteome. Untreated AML cell lines showed substantial overlap at all three omics level; however, while AZA treatment globally reduced DNA methylation in all cell lines, changes in the transcriptome and surface proteome were subtle and differed among the cell lines. Transcriptome analysis identified five commonly upregulated coding genes upon AZA treatment in all four cell lines, TRPM4 being the only gene encoding a surface protein, and surface proteomics analysis found no commonly regulated proteins. Gene Set Enrichment Analysis (GSEA) of differentially-regulated RNA and surface proteins showed a decrease in metabolism pathways and an increase in immune defense response pathways. As such, AZA treatmentled to diverse effects at the individual gene and protein level but converged to common responses at the pathway level. Given the heterogeneous responses in the four cell lines, the potential therapeutic strategies for AML in combinations with AZA are discussed.

ORGANISM(S): Homo sapiens

PROVIDER: GSE123207 | GEO | 2018/12/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Azacitidine treated AML cells reveals highly variable cell surface proteome remodeling [Illumina]

Project description:Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are diseases of abnormal hematopoietic differentiation with aberrant epigenetic alterations. Azacitidine (AZA) is a DNA methyltransferase inhibitor (DNMTi) widely used to treat MDS and AML, yet the impact of AZA on the cell surface proteome has not been defined. To identify potential therapeutic targets for use in combination with AZA in AML patients, we investigated the effects of AZA treatment on four AML cell lines representing different stages of differentiation. The effect of AZA treatment on these cell lines was characterized at three levels: the DNA methylome, the transcriptome, and the cell surface proteome. Untreated AML cell lines showed substantial overlap at all three omics level; however, while AZA treatment globally reduced DNA methylation in all cell lines, changes in the transcriptome and surface proteome were subtle and differed among the cell lines. Transcriptome analysis identified five commonly upregulated coding genes upon AZA treatment in all four cell lines, TRPM4 being the only gene encoding a surface protein, and surface proteomics analysis found no commonly regulated proteins. Gene Set Enrichment Analysis (GSEA) of differentially-regulated RNA and surface proteins showed a decrease in metabolism pathways and an increase in immune defense response pathways. As such, AZA treatmentled to diverse effects at the individual gene and protein level but converged to common responses at the pathway level. Given the heterogeneous responses in the four cell lines, the potential therapeutic strategies for AML in combinations with AZA are discussed.

2018-11-30 | GSE123140 | GEO

Multi-omics of azacitidine-treated AML cells reveals variable and convergent targets that remodel the cell surface proteome

Project description:Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are diseases of abnormal hematopoietic differentiation with aberrant epigenetic alterations. Azacitidine (AZA) is a DNA methyltransferase inhibitor (DNMTi) widely used to treat MDS and AML, yet the impact of AZA on the cell surface proteome has not been defined. To identify potential therapeutic targets for use in combination with AZA in AML patients, we investigated the effects of AZA treatment on four AML cell lines representing different stages of differentiation. The effect of AZA treatment on these cell lines was characterized at three levels: the DNA methylome, the transcriptome, and the cell surface proteome. Untreated AML cell lines showed substantial overlap at all three omics level; however, while AZA treatment globally reduced DNA methylation in all cell lines, changes in the transcriptome and surface proteome were subtle and differed among the cell lines. Transcriptome analysis identified five commonly up-regulated coding genes upon AZA treatment in all four cell lines, TRPM4 being the only gene encoding a surface protein, and surface proteomics analysis found no commonly regulated proteins. Gene Set Enrichment Analysis (GSEA) of differentially-regulated RNA and surface proteins showed a decrease in metabolism pathways and an increase in immune defense response pathways. As such, AZA treatment led to diverse effects at the individual gene and protein level but converged to common responses at the pathway level. Given the heterogeneous responses in the four cell lines, we discuss potential therapeutic strategies for AML in combinations with AZA.

2018-10-07 | MSV000083006 | MassIVE

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

LC-MSMS of the MHC-I immunopeptidome of AML cell lines

Project description:The hypomethylating agent 5-azacytidine (AZA) is the first-line induction therapy for AML patients unsuitable for intensive chemotherapy. The anti-tumor effect of AZA results in part from T-cell cytotoxic responses against MHC-I-associated peptides (MAPs) deriving from hypermethylated genomic regions such as cancer-testis antigens (CTAs), or endogenous retroelements (EREs). However, clear evidence supporting higher ERE MAPs presentation after AZA treatment in AML is lacking. Therefore, we examined the immunopeptidome of four AML cell lines treated with AZA through a proteogenomic approach to validate this hypothesis.

2024-04-17 | PXD038663 | Pride

RNA-seq of human AML, CMML and MDS CD34+ blast cells, CD4+ T cells and CD8+ T cells treated with 5-aza against untreated samples and healthy controls

Project description:This study includes 2 cohorts of samples. First cohort consists out of BM aspirates from 4 healthy individuals and 12 patients diagnosed with AML, MDS or CMML. Second cohort includes 5 healthy individuals and 17 patients diagnosed with AML, MDS or CMML. MDS and CMML patients were treated with 5-AZA on 6 cycles and samples were obtained before the treatment and 15 days after 1 and 6 rounds of treatment.

2019-12-10 | E-MTAB-8208 | biostudies-arrayexpress

Single-cell transcriptomes of CD8+ T cells from patients with HR-MDS and AML

Project description:Treatment with hypomethylating agents (HMA), and specifically azacitidine (AZA), is the standard of care for patients with higher-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) that are not eligible to receive intensive chemotherapy. Despite research efforts, it is not possible to predict response to treatment with HMA. In this study, we aimed to identify immune cell signatures in the bone marrow (BM) associated with treatment outcomes. By employing mass cytometry, we performed an in-depth immunophenotypic analysis in BM samples deriving from patients with myeloid neoplasms prior to treatment initiation. We identified an increased pre-treatment frequency of a CD8+ T cell subset, characterized as CD57+CXCR3+CCR7-CD45RA+, in patients with MDS and AML who did not respond to treatment with AZA, compared to responders. Furthermore, a baseline frequency of more than 29% of CD57+CXCR3+CD8+ T cells was correlated with poor overall survival. We further engaged scRNA-seq to assess the transcriptional profile of BM CD8+ T cells from treatment-naïve patients with MDS and AML, to identify molecular signatures in CD8+ T subpopulations associated with favorable outcomes. Response to treatment was positively associated with enrichment of IFN-mediated pathways coupled with enhanced cytotoxic signature, whereas enrichment of the TGF-β signaling pathway was observed in cell clusters from non-responders. Together, this study identified a specific CD57+CXCR3+ CD8+ T cell population with predictive value in patients with MDS and AML treated with AZA, and characterized molecular signatures in CD8+ T cells linked to cytokine signaling that were associated with treatment outcomes.

2024-01-12 | GSE250077 | GEO

Whole exome sequencing of human MDS/AML OCI-M2 and patient-derived bone marrow cell lines treated with 5-azacytidine

Project description:The whole exome sequencing experiment is part of the study: “Analysis of 5-azacytidine resistance models reveals a set of targetable pathways”. In the study we generated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) OCI-M2 cell lines as well as patient-derived bone marrow cell lines that are resistant to hypomethylating therapy by 5-azacytidine (AZA). By integrated analysis of expression and mutation data obtained from these samples we have identified multiple signaling pathways whose modulation by specific small molecule inhibitors significantly block proliferation of AZA-resistant cell lines without increasing their sensitivity to AZA. The understanding of the molecular mechanisms which characterize the AZA-R phenotype can be used for broadening therapeutic options at progressing states during AZA therapy.

2022-05-02 | E-MTAB-11172 | biostudies-arrayexpress

RNA-seq of human MDS/AML cell line OCI-M2 treated with 5-azacytidine and sulforaphane

Project description:The RNA sequencing experiment is part of the study: “Modulating Redox Balance Restores Azacytidine Efficacy in Hypomethylating Agent Resistant Disease.” In the study we generated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) OCI-M2 cell line that is resistant to hypomethylating therapy by 5-azacytidine (AZA). By modulation of the redox environment via modification of redox sensor KEAP1 using sulforaphane (SFN) in these cells we were able to restore sensitivity to AZA. We used RNA sequencing to define transcriptomic differences between AZA sensitive (AZA-S) and AZA resistant (AZA-R) cells and to characterize how the transcriptome is changing upon treatment of these cells with AZA, SFN and combination of both.

2021-07-16 | E-MTAB-10635 | biostudies-arrayexpress

A hypermethylated ALOX12 gene is highly susceptible to 5-azacytidine treatment in myelodysplastic syndromes

Project description:5-azacytidine (AZA) is widely used for treatment of myelodysplastic syndromes (MDS). However, identifying predictive factors for response to AZA remains challenging. The aim in present study was to identify the genes which are susceptible to AZA in MDS and investigate the possibility of the gene for predictor for response to AZA therapy. To identify AZA-susceptible genes, we compared the gene expression changes by AZA in MDS-L cells (AZA-sensitive) with those in MDS-L/CDA cells (AZA-resistant) in culture. Of 438 AZA-susceptible genes, we searched the genes which are hypermethylated in MDS patients as compared to healthy controls by analyzing public dataset GSE152710, and found ALOX12 gene. Analysis of public dataset GSE145733 and GSE58831 revealed that ALOX12 expression was suppressed in MDS classes with excess blasts but not in other classes, and were negatively and positively correlated with bone marrow blast counts and survival, respectively, in MDS patients. Analysis of public dataset GSE152710 revealed that the methylation level of ALOX12 gene was decreased in MDS patients with complete remission but not in those with partial response and progression disease after AZA therapy. Our retrospective clinical study in which nine AZA-treated patients were enrolled suggested that ALOX12 expression was increased in patients with favorable response, while decreased in patient with poor response after AZA therapy. In conclusion, ALOX12 gene could be tumor suppressive and promising marker for predicting the response to AZA therapy in MDS.

2023-05-31 | GSE233764 | GEO

Long term DNMT inhibition in SKM1 cells

Project description:SKM-1 cells were cultured for 28 days in the absence or presence of low doses of the DNMT1 inhibitors DAC (10 nM) or AZA (100 nM). The experiment was carried in two independent set at different times, and with 2 replicates for each condition (Ctl, AZA, DAC) for a total of 12 samples. The SKM-1 cell line is derived from secondary AML arising from MDS, and is one the few representative in vitro models of MDS.

2013-12-11 | E-MTAB-2130 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data