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Effects of DNA methyltransferase inhibitors (DNMTIs) on MDS-derived cell lines

ABSTRACT: To further investigate the action mechanisms of decitabine (DAC), the molecular pathways regulated by DAC were explored using the gene expression profile of MDS-L cells treated with 4 nM DAC or DMSO for 7 days. Genes whose expression changed by more than 2.0-fold following drug treatment were defined as regulated genes. 956 genes were up-regulated and 461 genes down-regulated in MDS-L cells treated with DAC (4 nM) as compared with the control. Gene expression profiling suggested that DAC significantly affects various gene biogroups, including cellular movement, inflammatory response, hematological system development and function, hematopoiesis, and cell death.

ORGANISM(S): Homo sapiens

PROVIDER: GSE39628 | GEO | 2012/09/01

SECONDARY ACCESSION(S): PRJNA171299

REPOSITORIES: GEO

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Effects of DNA methyltransferase inhibitors (DNMTIs) on MDS-derived cell lines

Project description:To further investigate the action mechanisms of decitabine (DAC), the molecular pathways regulated by DAC were explored using the gene expression profile of MDS-L cells treated with 4 nM DAC or DMSO for 7 days. Genes whose expression changed by more than 2.0-fold following drug treatment were defined as regulated genes. 956 genes were up-regulated and 461 genes down-regulated in MDS-L cells treated with DAC (4 nM) as compared with the control. Gene expression profiling suggested that DAC significantly affects various gene biogroups, including cellular movement, inflammatory response, hematological system development and function, hematopoiesis, and cell death. Decitabine-induced gene expression in MDS-L cells was measured after 7 days exposure at dose of 4 nM. Three independent samples.

2012-09-01 | E-GEOD-39628 | biostudies-arrayexpress

Effect of Decitabine on SKM-1 and MDS-L Gene Expression

Project description:In order to further study the mechanism of decitabine (DAC) on MDS cell lines, 1uM DAC was used to treat SKM-1 and MDS-L cell lines, and the molecular pathway changes regulated by DAC were explored. Genes whose expression changes more than 2.0 times after drug treatment are defined as regulated genes. Taking the intersection change of the two cell lines, it was found that compared with the control, 541 genes were up-regulated in the intersection of gene changes treated with DAC, and 762 genes were down-regulated. Gene expression profile analysis shows that DAC can significantly affect various cell biological processes, including antiviral response, immune response, inflammatory response and cell apoptosis.

2021-01-26 | GSE164744 | GEO

The impact of decitabine treatment in MDS-induced Tet2KD/KDEzh2Δ/Δ LSK HSPCs

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

Expression data comparing azacitidine and decitabine in non-small cell lung cancer lines

Project description:Azacitidine (AZA) and decitabine (DAC) are cytidine azanucleoside analogs with clinical activity in myelodysplastic syndromes (MDS) and potential activity in solid tumors. To better understand the mechanism of action of these drugs, we examined the effects of AZA and DAC in a panel of non-small cell lung cancer (NSCLC) cell lines. Of 5 NSCLC lines tested in a cell viability assay, all were sensitive to AZA (EC50 of 1.8M-bM-^@M-^S10.5 M-BM-5M), while only H1299 cells were equally sensitive to DAC (EC50 of 5.1 M-BM-5M). In the relatively DAC-insensitive cell line A549, both AZA and DAC caused DNA methyltransferase I depletion and DNA hypomethylation; however, only AZA significantly induced markers of DNA damage and apoptosis, suggesting that mechanisms in addition to, or other than, DNA hypomethylation are important for AZA-induced cell death. Cell cycle analysis indicated that AZA induced an accumulation of cells in sub-G1 phase, whereas DAC mainly caused an increase of cells in G2/M. Gene expression analysis of AZA- and DAC-treated cells revealed strikingly different profiles, with many genes distinctly regulated by each drug. In summary, while both AZA and DAC caused DNA hypomethylation, distinct effects were demonstrated on regulation of gene expression, cell cycle, DNA damage, and apoptosis. A549 and H1299 cells were treated with a dose range (0.3M-bM-^@M-^S3.0 M-NM-<M) of AZA or DAC for 48 hours, and effects on gene expression were assessed by microarray analysis.

2011-05-05 | E-GEOD-29077 | biostudies-arrayexpress

Gene expression profiling in primary AML cells treated with decitabine and cytarabine

Project description:Acute myeloid leukemia (AML), and other myeloid malignancies, are frequently treated with hypomethylating agents like decitabine. Alterations in the epigenome, induced by decitabine, are likely to result in gene expression changes. The effects of decitabine have not been systemically studied using primary AML samples. We cultured 18 different primary AML samples for 7 days, the last 3 days of which included 100 nM decitabine (DAC) or 100 nm cytarabine (AraC). We hypothesized that decitabine treatment would result in detectable and consistent gene expression changes. For comparison, we also analyzed mRNA from cells treated with DMSO control (mock) and mRNA from uncultured cells taken at the time of diagnosis.

2012-12-18 | E-GEOD-40442 | biostudies-arrayexpress

Gene expression changes following demethylation by 5-aza-2'-deoxycytidine（decitabine, DAC）in mouse T cell lymphoma EL4 cells

Project description:Our study had shown that DAC treatment enhanced immunogenecity of EL4 cells. To explore the mechanisms of DAC-induced tumor immunity, we carried out cDNA microarray analyses to compare the differential expression of genes between DAC and PBS treated EL4 cells. Two-condition experiment, PBS treated EL4 vs. Decitabine treated EL4 cells. Biological replicates: 3 PBS treated, 3 Decitabine treated, independently treatment and harvested. One replicate per array.

2013-02-15 | E-GEOD-38473 | biostudies-arrayexpress

Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment II

Project description:Decitabine (DAC) is used clinically for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells shows that mitotic regulation plays a pivotal role in DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations and antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, the overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation, while highlighting the potent activity of DAC to perturb mitosis through aberrant DNMT1-DNA covalent bonds.

2023-08-14 | GSE240570 | GEO

Expression data comparing azacitidine and decitabine in non-small cell lung cancer lines

Project description:Azacitidine (AZA) and decitabine (DAC) are cytidine azanucleoside analogs with clinical activity in myelodysplastic syndromes (MDS) and potential activity in solid tumors. To better understand the mechanism of action of these drugs, we examined the effects of AZA and DAC in a panel of non-small cell lung cancer (NSCLC) cell lines. Of 5 NSCLC lines tested in a cell viability assay, all were sensitive to AZA (EC50 of 1.8–10.5 µM), while only H1299 cells were equally sensitive to DAC (EC50 of 5.1 µM). In the relatively DAC-insensitive cell line A549, both AZA and DAC caused DNA methyltransferase I depletion and DNA hypomethylation; however, only AZA significantly induced markers of DNA damage and apoptosis, suggesting that mechanisms in addition to, or other than, DNA hypomethylation are important for AZA-induced cell death. Cell cycle analysis indicated that AZA induced an accumulation of cells in sub-G1 phase, whereas DAC mainly caused an increase of cells in G2/M. Gene expression analysis of AZA- and DAC-treated cells revealed strikingly different profiles, with many genes distinctly regulated by each drug. In summary, while both AZA and DAC caused DNA hypomethylation, distinct effects were demonstrated on regulation of gene expression, cell cycle, DNA damage, and apoptosis.

2011-05-05 | GSE29077 | GEO

Gene expression profiling of myelodysplastic CD34+ hematopoietic stem cells treated in vitro with decitabine

Project description:Epigenetic mechanisms contribute to deregulated gene expression of hematopoietic progenitors in Myelodysplastic Syndromes (MDS). Hypomethylating agents are able to improve peripheral cytopenias in MDS patients. To identify critical gene expression changes induced by hypomethylating agents, we analyzed gene expression profiling (GEP) of myelodysplastic and normal CD34+ hematopoietic stem cells treated in vitro with or without decitabine. Four MDS and two untreated early stage Hodgkin’s lymphomas were analyzed for GEP. Mock treated CD34+ stem cells segregate according to diagnosis and karyotype. After decitabine treatment, gene expression changes were more consistent on MDS CD34+ cells with abnormal kayotype. Comparing decitabine-induced genes with those found down-regulated in mock-treated MDS cells, we identified a list of candidate tumor suppressor genes in MDS. By real-time RT-PCR we confirmed expression changes for three selected genes CD9, CXCR4 and GATA2 in 12 MDS patients and 4 controls. CD9 was widely repressed in most MDS CD34+ cell samples, although similar levels of methylation were found in both normal and MDS total bone marrows. CXCR4 promoter methylation was absent in total bone marrows from 36 MDS patients. In conclusion, changes in gene expression changes induced by hypomethylating treatment are more pronounced in CD34+ cells from abnormal karyotype.

2009-12-23 | GSE19610 | 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

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