Serial sequencing of MDS patients during Azacitidine treatment
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ABSTRACT:
PROVIDER: PRJEB18013 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR1767400.fastq.gz | Fastqsanger.gz | |||
| ERR1767400_1.fastq.gz | Fastqsanger.gz | |||
| ERR1767400_2.fastq.gz | Fastqsanger.gz | |||
| ERR1767410.fastq.gz | Fastqsanger.gz | |||
| ERR1767410_1.fastq.gz | Fastqsanger.gz |
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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
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.
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Project description:Hypomethylating agents are used as frontline therapy for myelodysplastic neoplasms (MDS), but clinical response is unpredictable. To determine whether response was associated with in vivo dynamics of DNA hypomethylation, we conducted a phase 2 trial for MDS using both injection and oral azacitidine (AZA). We established that global DNA methylation levels in peripheral blood and bone marrow mononuclear cells were comparable in AZA responders and non-responders during their course of treatment. However, there were distinct baseline and early drug induced differences in CpG methylation in haematopoietic stem and progenitor cells (HSPCs) in responders compared to non-responders that overlapped with regulatory regions of genes associated with tissue patterning, cell migration and myeloid differentiation. Following six cycles of therapy when clinical response typically manifests, differential hypomethylation in responder HSPCs pointed to marrow adaptation as a driver of enhanced haematopoiesis. Taken together, CpG methylation differences in HSPCs may explain variable response to AZA.
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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.
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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.
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