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.
2016-02-10 | GSE77750 | GEO
Project description:Determine the differences in gene expression profiles of MV-4-11 AML cells treated with HDAC1/2-selective inhibition, azacitidine, or the combination of the two agents. Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic stem cell disorders characterized by defects in myeloid differentiation and increased proliferation of neoplastic hematopoietic precursor cells. Outcomes for patients with AML remain poor, highlighting the need for novel treatment options. Aberrant epigenetic regulation plays an important role in the pathogenesis of AML, and inhibitors of DNA methyltransferase or histone deacetylase (HDAC) enzymes have exhibited activity in preclinical AML models. Combination studies with HDAC inhibitors plus DNA methyltransferase inhibitors have suggested beneficial clinical activity in AML, however the toxicity profiles of non-selective HDAC inhibitors in the combination setting limit their clinical utility. In this work, we describe the preclinical development of selective inhibitors of HDAC1 and HDAC2, which are hypothesized to have improved safety profiles, for combination therapy in AML. We demonstrate that selective inhibition of HDAC1 and HDAC2 is sufficient to achieve efficacy both as a single agent and in combination with azacitidine in preclinical models of AML, including established AML cell lines, leukemia cells from AML patient bone marrow samples and in vivo xenograft models of human AML. Gene expression profiling of AML cells treated with either an HDAC1/2 inhibitor, azacitidine, or the combination of both have identified a list of genes involved in transcription and cell cycle regulation as potential mediators of the combinatorial effects of HDAC1/2 inhibition with azacitidine. Together, these findings support the clinical evaluation of selective HDAC1/2 inhibitors in combination with azacitidine in AML 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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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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Project description:PANTHER is a global, randomized phase 3 trial of pevonedistat+azacitidine (n = 227) vs azacitidine monotherapy (n = 227) in patients with newly diagnosed higher-risk myelodysplastic syndromes (MDS; n = 324), higher-risk chronic myelomonocytic leukemia (n = 27), or acute myeloid leukemia (AML) with 20% to 30% blasts (n = 103). The primary end point was event-free survival (EFS). In the intent-to-treat population, the median EFS was 17.7 months with pevonedistat+azacitidine vs 15.7 months with azacitidine (hazard ratio [HR], 0.968; 95% confidence interval [CI], 0.757-1.238; P = .557) and in the higher-risk MDS cohort, median EFS was 19.2 vs 15.6 months (HR, 0.887; 95% CI, 0.659-1.193; P = .431). Median overall survival (OS) in the higher-risk MDS cohort was 21.6 vs 17.5 months (HR, 0.785; P = .092), and in patients with AML with 20% to 30% blasts was 14.5 vs 14.7 months (HR, 1.107; P = .664). In a post hoc analysis, median OS in the higher-risk MDS cohort for patients receiving >3 cycles was 23.8 vs 20.6 months (P = .021) and for >6 cycles was 27.1 vs 22.5 months (P = .008). No new safety signals were identified, and the azacitidine dose intensity was maintained. Common hematologic grade ≥3 treatment emergent adverse events were anemia (33% vs 34%), neutropenia (31% vs 33%), and thrombocytopenia (30% vs 30%). These results underscore the importance of large, randomized controlled trials in these heterogeneous myeloid diseases and the value of continuing therapy for >3 cycles. The trial was registered on clinicaltrials.gov as #NCT03268954.
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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:Methylation data for MDS bone marrow derived MSCs before and after 5-Azacitidine treatment. Methylation profiles were measured using the Infinium Human MethylationEPIC BeadChip (Illumina). There are 5 healthy MSC and 8 high-risk MDS-MSC samples, untreated and treated with 5-Azacitidine in vitro.
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