Analysis of chromatin accessibility relative to epigenetic features of azacitidine response in high-risk myelodysplastic syndrome
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PROVIDER: PRJNA1235117 | ENA |
REPOSITORIES: ENA
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Project description:Azacitidine is used to treat patients with myelodysplastic syndrome, which alters epigenetic regulatory program that changes global gene expression by inhibiting DNA methylation. However, epigenomic factors affecting azacitidine response have not been studied in the context of chromatin. The efficacy of the hypomethylating agent differs by patient, leaving approximately 40% of patients fail to respond. Here, we demonstrate that chromatin accessibility features in patient-derived bone marrow cells can distinguish azacitidine responders from non-responders before treatment. Profiling chromatin accessibility from 23 high-risk myelodysplastic syndrome patients discovered that treatment response is strongly associated with distinct hematopoietic cell states. While non-responders showed enrichment of myeloid progenitor signatures, responders were characterized by elevated T cell populations. Notably, CD8+ T cells from non-responders exhibited selective loss of chromatin accessibility at TBX/EOMES binding sites, revealing a previously unrecognized link between T cell differentiation state and azacitidine response. These findings suggest the importance of immune cell differentiation and their activity in hypomethylating agent response for myelodysplastic syndromes, providing insights for patient stratification and treatment optimization based on the chromatin accessibility in high-risk myelodysplastic syndrome patients.
2025-07-10 | GSE291718 | GEO
Project description:Azacitidine Modulates the Mesenchymal Stromal Cell Compartment in Myelodysplastic Syndromes
| PRJNA447430 | ENA
Project description:Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response. We performed global methylation analysis of 75 patients with high risk MDS and secondary AML (sAML) who were included in CETLAM MDS-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetics. At diagnosis, no global methylation pattern allowed us to differentiate patients according to the cytological subtype, cytogenetics or treatment response. But we found a methylation signature defined by 200 probes, which allowed us to distinguish between responding and non-responding patients to azacitidine (AZA) treatment. Studying follow-up samples, we have confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to determine a methylation pattern predictive of progression or relapse. In conclusion, altered DNA methylation patterns at diagnosis, in a subset of determined CpGs, may serve as biomarker for predicting AZA response.
2021-01-27 | GSE152710 | GEO
Project description:Genome-wide expression and methylation profiling identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes (MDSs). Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases. Low-risk MDS patients and age-matched controls without haematological malignancies were included in the study. Mononuclear cells were isolated from bone marrow samples of low-risk MDS patients and controls by density gradient (Ficoll). A cohort of 18 patients with low-risk MDS and seven controls were included in a simultaneous integrative study of methylation and expression, while the whole series was used as a control group of expression data.
2012-09-25 | E-GEOD-41130 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE41130: Expression profiling of Low-Risk Myelodysplastic Syndromes (MDSs) GSE41215: Methylation profiling of Low-Risk Myelodysplastic Syndromes (MDSs) Refer to individual Series
2012-09-28 | E-GEOD-41216 | biostudies-arrayexpress
Project description:Genome-wide expression and methylation profiling identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes (MDSs). Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases. Low-risk MDS patients and age-matched controls without haematological malignancies were included in the study. Mononuclear cells were isolated from bone marrow samples of low-risk MDS patients and controls by density gradient (Ficoll). A cohort of 18 patients with low-risk MDS and seven controls were included in a simultaneous integrative study of methylation (using Methylated CpG Island Amplification and Microarrays, MCAM) and expression (using Affymetrix microarrays HG-U133 Plus 2), while the whole series was used as a control group of expression data.
2012-09-28 | E-GEOD-41215 | biostudies-arrayexpress
Project description:Genome-wide expression and methylation profiling identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes (MDSs). Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases.
2012-09-25 | GSE41130 | GEO
Project description:Genome-wide expression and methylation profiling identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes (MDSs). Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases.
2012-09-28 | GSE41215 | GEO
Project description:The nucleotide analogue azacitidine 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. We performed an optimized loss-of-function shRNA screen in combination with azacitidine treatment in an MDS-derived acute myeloid leukemia cell line to identify chromatin regulators affecting drug response. We identified CBP, as a major regulator of azacitidine sensitivity. Compounds inhibiting the enzymatic activity of CBP synergistically reduced viability of MDS-derived AML cell lines when combined with AZA. Surprisingly, this effect 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 cell cycle progression.
2021-09-10 | GSE158813 | GEO
Project description:The nucleotide analogue azacitidine 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. We performed an optimized loss-of-function shRNA screen in combination with azacitidine treatment in an MDS-derived acute myeloid leukemia cell line to identify chromatin regulators affecting drug response. We identified CBP, as a major regulator of azacitidine sensitivity. Compounds inhibiting the enzymatic activity of CBP synergistically reduced viability of MDS-derived AML cell lines when combined with AZA. Surprisingly, this effect 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 cell cycle progression.
2021-09-10 | GSE158738 | GEO