Single-cell proteogenomics of MDS upon AZA
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ABSTRACT:
PROVIDER: EGAS00001007427 | EGA |
REPOSITORIES: EGA
Similar Datasets
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
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
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
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
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
Project description:Treatment with the hypomethylating agent 5-azacytidine (AZA) increases survival in high-risk (HR) myelodysplastic syndrome (MDS) patients, but predicting patient response and overall survival remains challenging. To address these issues, we analyzed mutational and transcriptional profiles in CD34+ hematopoietic stem/progenitor cells (HSPCs) before and following AZA therapy in MDS patients. AZA treatment led to a greater reduction in the mutational burden in both blast and hematological responders than non-responders. Blast and hematological responders showed transcriptional evidence of pre-treatment enrichment for pathways such as oxidative phosphorylation, MYC targets, and mTORC1 signaling. While blast non-response was associated with TNFa signaling and leukemia stem cell signature, hematological non-response was associated with cell-cycle related pathways. AZA induced similar transcriptional responses in MDS patients regardless of response type. Comparison of blast responders and non-responders to normal controls, allowed us to generate a transcriptional classifier that could predict AZA response and survival. This classifier outperformed a previously developed gene signature in a second MDS patient cohort, but signatures of hematological responses were unable to predict survival. Overall, these studies characterize the molecular consequences of AZA treatment in MDS HSPCs and identify a potential tool for predicting AZA therapy responses and overall survival prior to initiation of therapy.
2024-07-21 | GSE272173 | GEO
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
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
Project description:To evaluate the impact of DNA demethylating agents on our mouse MDS model, we chose 5-aza-2’-deoxycytidine, decitabine (DAC), one of the DNA demethylating agents, which is incorporated into DNA but not RNA and has 10-fold more potency in DNA demethylation than 5-azacitidine. We transplanted Tet2KD/KDEzh2Δ/Δ MDS cells into lethally irradiated secondary recipients and treated them with DAC (low dose DAC at 0.25mg/kg, 3 times a week, intraperitoneal injection), then purified LSK HSPCs and evaluated the expression profiles.
2017-03-15 | GSE79204 | GEO
Project description:We performed high-throughput single-cell targeted DNA and surface protein sequencing (scDNA + protein-seq) using the Mission Bio Tapestri Platform to analyze NK cells isolated from five patients with CCUS exhibiting different genetic alterations. Our analysis revealed that the NK cells were part of the mutant clone population, displaying a clonal burden comparable to that observed in the myeloid cells of the same patients. This dataset provides valuable insights into the clonal architecture of NK cells in the context of CCUS.
2024-09-09 | GSE276492 | GEO