Vitamin C promotes anti-leukemia of DZNep in Acute Myeloid Leukemia
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ABSTRACT:
PROVIDER: PRJNA792424 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17332915.fastq.gz | Fastqsanger.gz | |||
| SRR17332916.fastq.gz | Fastqsanger.gz | |||
| SRR17332917.fastq.gz | Fastqsanger.gz | |||
| SRR17332918.fastq.gz | Fastqsanger.gz | |||
| SRR17332919.fastq.gz | Fastqsanger.gz |
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Project description:The epigenetic treatment by 3-Deazaneplanocin A (DZNep), a histone methyltransferase inhibitor, shows great potential against acute myeloid leukemia (AML). However, the variant sensitivity and incomplete response to DZNep are commonly observed. We reveal that vitamin C (Vc) dramatically promotes DZNep response against leukemic cells in different cell lines and primary AML samples. To examine the molecular determinants underlying Vc enhanced anti-leukemia effect of DZNep, we conducted a genome-wide RNA sequencing and a gene ontology (GO) enrichment analysis of differentially expressed mRNAs in each group was performed.
2022-09-30 | GSE192629 | GEO
Project description:Vitamin B6 addiction in acute myeloid leukemia
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Project description:We and others have previously reported that 3-Deazaneplanocin A (DZNep) is a histone methylation inhibitor that has a wide range anticancer effects in a variety of human cancers. Here, using acute myeloid leukemia as a model, we reported a less toxic analog of DZNep, named D9, that is shown to be efficacious in both cell lines and patient samples of AML. Gene expression analysis in a panel of AML cell lines treated with D9 identified a set of genes that is associated with D9 sensitivity and is implicated in multiple oncogenic signaling pathways. Moreover, we show that D9 is able to deplete the leukemia stem cells (LSC) and abolish chemotherapy-induced LSC enrichment, leading to dramatic elimination of AML cell survival and associated gene expression when combined with chemotherapy. Thus, D9 appears to be a robust epigenetic compound that may constitute a potential for AML therapy.
2015-12-31 | GSE59625 | GEO
Project description:We and others have previously reported that 3-Deazaneplanocin A (DZNep) is a histone methylation inhibitor that has a wide range anticancer effects in a variety of human cancers. Here, using acute myeloid leukemia as a model, we reported a less toxic analog of DZNep, named D9, that is shown to be efficacious in both cell lines and patient samples of AML. Gene expression analysis in a panel of AML cell lines treated with D9 identified a set of genes that is associated with D9 sensitivity and is implicated in multiple oncogenic signaling pathways. Moreover, we show that D9 is able to deplete the leukemia stem cells (LSC) and abolish chemotherapy-induced LSC enrichment, leading to dramatic elimination of AML cell survival and associated gene expression when combined with chemotherapy. Thus, D9 appears to be a robust epigenetic compound that may constitute a potential for AML therapy.
2015-12-31 | GSE59624 | GEO
Project description:We and others have previously reported that 3-Deazaneplanocin A (DZNep) is a histone methylation inhibitor that has a wide range anticancer effects in a variety of human cancers. Here, using acute myeloid leukemia as a model, we reported a less toxic analog of DZNep, named D9, that is shown to be efficacious in both cell lines and patient samples of AML. Gene expression analysis in a panel of AML cell lines treated with D9 identified a set of genes that is associated with D9 sensitivity and is implicated in multiple oncogenic signaling pathways. Moreover, we show that D9 is able to deplete the leukemia stem cells (LSC) and abolish chemotherapy-induced LSC enrichment, leading to dramatic elimination of AML cell survival and associated gene expression when combined with chemotherapy. Thus, D9 appears to be a robust epigenetic compound that may constitute a potential for AML therapy. We found D9 treatment depleted chemotherapy-induced LSC. We next sought to characterize the molecular changes induce by the chemotherapy that is antagonized by D9. To do this, TF-1a cells before and after Ara-C or ADR treatment or co-treated with D9 were harvested for RNA isolation and genome-wide transcription profilling.
2015-12-31 | E-GEOD-59625 | biostudies-arrayexpress
Project description:The genomes of myeloid malignancies are characterized by epigenomic abnormalities. Heterozygous, inactivating TET2 mutations and neomorphic IDH mutations are recurrent and mutually exclusive in acute myeloid leukemia (AML) genomes. Ascorbic Acid (vitamin C) has been shown to stimulate the catalytic activity of TET2 in vitro and thus we sought to explore its effect in a leukemic model expressing IDH1R132H. Vitamin C treatment induced an IDH1R132H dependent reduction in cell proliferation and an increase in expression of genes involved in leukocyte differentiation. Vitamin C induced differentially methylated regions (DMRs) that displayed a significant overlap with enhancers implicated in myeloid differentiation and were enriched in sequence elements for the hematopoietic transcription factors RUNX1 and PU.1. ChIP-seq of PU.1 and RUNX1 revealed a significant loss of PU.1 and increase of RUNX1 bound DNA elements accompanied by their demethylation following vitamin C treatment. Additionally, vitamin C induced an increase in H3K27ac flanking sites bound by RUNX1. Based on these data we propose a model of vitamin C induced epigenetic remodelling of transcription factor binding sites driving differentiation in a leukemic model.
2017-07-01 | GSE87623 | GEO
Project description:The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with DZNep and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM.
2011-07-04 | GSE26921 | GEO
Project description:We and others have previously reported that 3-Deazaneplanocin A (DZNep) is a histone methylation inhibitor that has a wide range anticancer effects in a variety of human cancers. Here, using acute myeloid leukemia as a model, we reported a less toxic analog of DZNep, named D9, that is shown to be efficacious in both cell lines and patient samples of AML. Gene expression analysis in a panel of AML cell lines treated with D9 identified a set of genes that is associated with D9 sensitivity and is implicated in multiple oncogenic signaling pathways. Moreover, we show that D9 is able to deplete the leukemia stem cells (LSC) and abolish chemotherapy-induced LSC enrichment, leading to dramatic elimination of AML cell survival and associated gene expression when combined with chemotherapy. Thus, D9 appears to be a robust epigenetic compound that may constitute a potential for AML therapy. We evaluated the overall effects of D9 on histone lysine methylations in AML cell lines and its relationship to apoptosis induction by D9. The results demonstrated that the both sensitive and resistant cell lines, treated with D9 for 48 and 72 hours, showed similar levels of suppression of histone lysine methylation. Thus, the differential sensitivities of AML cells to D9 is not due to its different ability to inhibit the bulk histone methylation but is more likely to be associated with the differential gene expression response to D9. To test this hypothesis, we treated three sensitive (MOLM-14, MV4-11 and TF-1) and three resistant (Mono-Mac-1, THP-1, and KG-1a) cell lines with D9 at 1 or 5 μM for 48 hours and performed Illumina BeadChip transcriptom profiling analysis. Significance Analysis of Microarrays (SAM) analysis shows that D9 treatment resulted in transcriptional changes of 547 genes, including 327 upregulated genes and 220 downregulated genes in sensitive cell lines but not in resistant cell lines.
2015-12-31 | E-GEOD-59624 | biostudies-arrayexpress
Project description:The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with DZNep and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM. Cells were treated with 0.5 μmol/L DZNep for 48 h. Total RNA was extracted by using the Qiagen RNeasy Mini kit (Germany). Gene expression was performed using the GeneChip® Human Genome U133A Array (Affymetrix) following the manufacturer’s instructions. Data analysis was performed using GeneSpring software from Agilent Technologies.
2011-07-04 | E-GEOD-26921 | biostudies-arrayexpress