Epigenetically regulated expression of ALDH1 by anthracyclines causes an adaptive oxidative response and drug resistance in AML
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE295068 | GEO | 2025/12/03
REPOSITORIES: GEO
Similar Datasets
Project description:Epigenetically regulated expression of ALDH1 by anthracyclines causes an adaptive oxidative response and drug resistance in AML
| PRJNA1252749 | ENA
Project description:Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR) but not the nucleoside analog Cytarabine, the two main drugs used to treat Acute Myeloid Leukemia (AML), induces rapid (3 hours) and broad transcriptional changes in AML cells. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, in particular at active promoters and enhancers. Surprisingly, accelerating deSUMOylation dampens DNR-induced transcriptional reprogramming. Quantitative proteomics shows that proteins that are deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. Although DNR does not modify CTCF binding on chromatin in general and at NFKB2 promoter in particular, it leads to a SUMO-dependent reconfiguration of chromatin loops engaging CTCF- and SUMO-bound NFKB2 promoter with distal cis-regulatory regions.
2023-06-23 | GSE231023 | GEO
Project description:Daunorubicin (DNR) and Cytarabin (Ara-C) are the main chemotherapeutic drugs used for Acute Myeloid Leukemias (AML) treatment. However, their mode of action is not well understood. To decipher if these drug would induce rapid transcriptional reprogramming, we treated HL-60 AML cell line with DNR or Ara-C for 3 hours and carried out a transcriptomic analyses. In addition, we had shown that Reactive Oxigen Species (ROS) produced by NADPH oxidases (NOX) are involved in DNR-induced gene expression. We therefore also performed a transcriptomic analyses in HL-60 cells treated with DNR and VAS2870, an NADPH oxidase inhibitor. HL-60 cells were treated or not for 3 hours with 2 µM Ara-C, 1 µM DNR or 1 µM DNR + 20µM VAS 2870. RNAs were purified from 3 independent experiments and used to probe Affymetrix Human Gene 2.0 ST Genechips
2017-12-31 | E-MTAB-4895 | biostudies-arrayexpress
Project description:Resistance to chemotherapy is one of the most relevant aspects of treatment failure in cancer. Cell lines are used as models to study resistance. We analyze the transcriptional profile of two multidrug resistant (MDR) cell lines (Lucena 1 and FEPS) derived from the same drug-sensitive cell K562. Microarray data identified 130 differentially expressed genes (DEG) between K562 vs Lucena, 1,932 between K562 vs FEPS, and 1,211 between Lucena 1 versus FEPS. The NOTCH pathway was affected in FEPS with overexpression of NOTCH2 and HEY1. The highly overexpressed gene in MDR cell was ABCB1, and both presented the ABCB1 promoter unmethylated. Gene expression profiles were obtained with the GeneChip® Human Genome U133 Plus 2.0 Array (Affymetrix, Singapore) according to the manufacturer´s instructions; all hybridization experiments were carried out in duplicate. The following samples were analyzed: human K562 cell line RNA from cells grown without drugs; human Lucena 1 cell line RNA from cells grown in medium with vincristine (Lucena 1+VCR); Lucena 1 cell line RNA from cells grown in medium without drugs (Lucena 1-VCR); human FEPS cell line RNA from cells grown in medium with daunorubicin (FEPS +DNR), and FEPS cell line RNA from cells grown in medium without drugs (FEPS -DNR).Comparisons of microarray expression data were carried out between K562 vs Lucena 1 grown in medium without vincristine; K562 vs FEPS grown in medium without daunorubicin; Lucena 1 grown in medium without vincristine vs FEPS grown in medium without daunorubicin. Additionally, we compared expression profiles of each multidrug resistant cell line (Lucena 1 and FEPS) grown in different conditions: Lucena 1 grown in medium without vincristine vs Lucena 1 grown in medium with vincristine, and FEPS grown in medium without daunorubicin vs FEPS grown in medium with daunorubicin.
2015-01-01 | E-GEOD-57470 | biostudies-arrayexpress
Project description:Wide inter-individual variation in terms of outcome and toxic side effects of treatment exist among patients with AML receiving chemotherapy with cytarabine (Ara-C) and daunorubicin (Dnr). Drug resistance and relapse are considered major causes of treatment failure. Gene expression profiling was undertaken to address possible mechanisms of Ara-C/Dnr resistance. Based on ex vivo Ara-C cytotoxicity at diagnosis, Ara-C sensitive (IC50 <3uM AraC) and Dnr sensitive samples (IC50 < 0.5 uM) (5 samples each) were included for microarray analysis. These were compared with the samples which were drug resistant ex vivo at diagnosis. Our microarray experiment resulted in indentifying differentially expressed genes under ex vivo Ara-C sensitive as well as Dnr sensitive samples compared to ex vivo Drug resistant samples.
2016-01-02 | GSE52919 | GEO
Project description:Wide inter-individual variation in terms of outcome and toxic side effects of treatment exist among patients with AML receiving chemotherapy with cytarabine (Ara-C) and daunorubicin (Dnr). Drug resistance and relapse are considered major causes of treatment failure. Gene expression profiling was undertaken to address possible mechanisms of Ara-C/Dnr resistance. Based on ex vivo Ara-C cytotoxicity at diagnosis, Ara-C sensitive (IC50 <3uM AraC) and Dnr sensitive samples (IC50 < 0.5 uM) (5 samples each) were included for microarray analysis. These were compared with the samples which were drug resistant ex vivo at diagnosis. Our microarray experiment resulted in indentifying differentially expressed genes under ex vivo Ara-C sensitive as well as Dnr sensitive samples compared to ex vivo Drug resistant samples. One-color experiment,Organism: Homo sapiens, Custom Human Whole Genome 8x60k Array designed by Genotypic Technology Private Limited (AMADID: 27114), Labeling kit: Agilent Quick-Amp labeling Kit (p/n5190-0442)
2016-07-04 | E-GEOD-52919 | biostudies-arrayexpress
Project description:TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.
2024-02-01 | GSE243674 | GEO
Project description:The Acute Myeloid Leukemia cell line HL-60 was rendered resistant to daunorubicin (DNR) or cytarabine (Ara-C) by continuous exposure to the drug up to concentrations of 30nM for DNR and 100nM for Ara-C. Transcriptomic analysis were then performed by RNA-Seq to compare the cell lines
2022-01-08 | GSE193094 | GEO
Project description:Acute myeloid leukemia (AML) originates from malignant, immature myeloid progenitor cells that differentiate into dysfunctional myeloblasts. While cytarabine (Ara-C) and daunorubicin (DNR)-based chemotherapy regimens are the standard treatments, approximately 10-40% of AML patients under the age of 60 and 40-60% over 60 do not respond, leading to refractory or relapsed (R/R) AML. Targeted chemotherapy for FLT3-ITD mutated R/R AML cells improves response rates and survival outcomes in FLT3-ITD mutated R/R AML patients. However, patients with wild-type FLT3 R/R AML remain therapeutically challenged, with persistent difficulty in finding effective treatments. Better insights on the fundamental understanding of treatment failure in wild-type FLT3 AML cells are needed to enhance therapeutic outcomes. However, precise mechanisms behind the treatment failure remain unclear. This study investigates the mechanisms underlying the failure of Ara-C and DNR-based chemotherapy in wild-type FLT3 R/R AML. Using RHI-1 cells, a wild-type FLT3 AML cell line with Ara-C resistance, we demonstrated that Ara-C resistance-mediated DNR tolerance did not result from reducing the concentration of DNR in RHI-1 cells, but rather from interrupting the cytotoxic mechanisms of DNR through the Ara-C resistance of RHI-1. The down-regulated deoxycytidine kinase (DCK) in RHI-1 cells interrupted mechanisms of Ara-C cytotoxic action. Also, the down-regulation of DCK enhanced mitochondrial metabolic pathways, DNA repair process, and ROS detoxification. Through these pathways, RHI-1 cells exhibit tolerance under DNR treatment. Among these enhanced processes, targeting mitochondrial metabolism, particularly OXPHOS complex I proteins, improved the efficacy of both Ara-C and DNR. Our findings shed light on a potential mechanism underlying the treatment failure and the role of mitochondrial metabolism in wild-type FLT3 R/R AML cells.
2025-05-07 | PXD054797 | Pride
Project description:Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces broad transcriptional changes in AML cells before cell death induction. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, which limits both the positive and negative effects of DNR on transcription. Quantitative proteomics shows that proteins that are deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. Its induction is preceded by a SUMO-dependent reconfiguration of chromatin loops engaging its CTCF- and SUMO-bound promoter with distal cis-regulatory regions. Altogether, our work suggests that one of the earliest effects of DNR in AML cells is a SUMO-dependent transcriptional reprogramming.
2023-06-23 | PXD032956 | Pride