Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA255782 | ENA |
REPOSITORIES: ENA
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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. 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: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 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:D9, a novel 3-Deazaneplanocin A (DZNep) analog, is efficacious in targeting acute myeloid leukemia (AML) (Sensitive vs Resistance)
| PRJNA255781 | ENA
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:We demonstrated that 3-Deazaneplanocin A (DZNep), a histone methyltransferase inhibitor, induce robust apoptosis in AML cells through increased ROS production and ER stress. We identified a core gene signature including TXNIP, a major redox control molecule which is crucial in DZNep-induced apoptosis. MOLM-14 cells were treated with DMSO and DZNep 2 µM for 24 hours
2011-07-01 | E-GEOD-30315 | biostudies-arrayexpress
Project description:We demonstrated that 3-Deazaneplanocin A (DZNep), a histone methyltransferase inhibitor, induce robust apoptosis in AML cells through increased ROS production and ER stress. We identified a core gene signature including TXNIP, a major redox control molecule which is crucial in DZNep-induced apoptosis.
2011-07-01 | GSE30315 | GEO
Project description:Background:Aberrant DNA methylation that silences tumor suppressor genes occurs frequently in patients with acute myeloid leukemia (AML). Treatment of AML patients with the inhibitor of DNA methylation, 5-aza-2'-deoxycytidine (5-AZA-CdR) can induce complete remissions, but most patients will relapse. The clinical efficacy of 5-AZA-CdR may be influenced by its limited capacity to activate tumor suppressor genes silenced by methylation of lysine 27 histone H3 (H3K27) by EZH2. In order to overcome this limitation, we investigated previously the antileukemic action of 5-AZA-CdR in combination with the EZH2 inhibitor, 3-deazaneplanocin A (DZNep) on HL-60 AML cells. We observed a remarkable synergistic interaction against these AML cells for this combination. In this study, we investigated in more depth the action of 5-AZA-CdR plus DZNep on gene expression in AML cells using RNA sequence analysis Result:In a colony assay, 5-AZA-CdR in combination with DZNep exhibited also a potent synergy against another human AML cell line: AML-3. The induction of apoptosis in HL-60 and AML3 leukemic cells by 5-AZA-CdR plus DZNep was also synergistic. RNA sequence analysis on HL-60 leukemic cells showed that the combination of 5-AZA-CdR plus DZNep increased the expression of thousands of genes. The genes upregulated by this combination included genes related to differentiation, development, senescence, apoptosis, and tumor suppressor function. Many of the genes activated by 5-AZA-CdR plus DZNep have the potential to suppress leukemogenesis. Conclusion: The activation of many genes by the combination of 5-AZA-CdR plus DZNep correlates with its synergistic antileukemic action. The block in differentiation is one of the hallmarks of AML.The activation of many genes that program differentiation and development by this combination of epigenetic agents has the potential to reverse this block. The reversal of these two epigenetic genesilencing mechanisms by 5-AZA-CdR plus DZNep merits clinical investigation in patients with AML
2017-02-01 | GSE94344 | GEO
Project description:This report explores the effect of Hif-1alpha deletion, using a conditional mouse model, together with standard chemotherapy regimen to evaluate leukemia stem cell (LSC) targeting in a murine model of MLL-AF9 driven acute myeloid leukemia (AML). This study reveals that Hif-1alpha-deleted leukemias displayed a faster disease progression after chemotherapy.
2019-01-23 | GSE119484 | GEO