Opioid agonists as potential AML therapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA615085 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-03-20 | GSE147511 | GEO
Project description:Acute myeloid leukemia (AML) is a type of heterogeneous and fatal hematopoietic malignancy. The ten-eleven translocation (TET) mediated DNA demethylation is known to be critically associated with AML pathogenesis. Through chemical compound screening, we found that the opioid receptor agonist, loperamide hydrochloride (OPA1), significantly suppresses AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, were then verified in AML cells in vitro, and t(11q23) and t(8;21) AML mouse models in vivo. OPA1-induced activation of OPRM1 enhanced the transcription of TET2, increased DNA 5-hydroxymethylcytosine (5hmC) modification, and in turn, activated NFκB signaling. Notably, AML with TET2 mutations or chemotherapy resistance were highly sensitive to OPA1. Our results reveal a previously unknown OPRM1-TET2-5hmC-TRAF2 regulatory axis in AML, and suggest that opioid agonists, particularly OPA1, an FDA-approved antidiarrheal drug, have therapeutic potential in AML, especially in TET2 mutated and chemotherapy-resistant AML, which have a poor prognosis.
2024-01-19 | GSE165803 | GEO
Project description:Acute myeloid leukemia (AML) is a group of heterogeneous diseases with high malignancy. The ten-eleven translocation (TET) mediated DNA demethylation was known to be critically associated with AML pathogenesis. Through chemical compound screening, we found an opioid receptor agonist, namely loperamide hydrochloride (OPA1), most significantly suppressed AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, were then verified in AML cells in vitro, and AML mouse models carrying t(11q23) and t(8;21) in vivo. OPA1-induced activation of OPRM1 enhanced the transcription of TET2, increased DNA 5-hydroxymethylcytosine (5hmC) modification, and in turn, activated NFκB signaling. Notably, AML with TET2 mutations or chemotherapy resistance were sensitive to OPA1. Our results unveiled the previously unappreciated OPRM1-TET2-5hmC-TRAF2 regulatory axis in AML, and highlighted the therapeutic potential of opioid agonists, particularly OPA1, a FDA-approved antidiarrheal drug, in treating AML, especially TET2 mutated AML and chemotherapy-resistant AML, which were known to have poor prognosis.
2023-03-20 | GSE147509 | GEO
Project description:Acute myeloid leukemia (AML) is a group of heterogeneous diseases with high malignancy. The ten-eleven translocation (TET) mediated DNA demethylation was known to be critically associated with AML pathogenesis. Through chemical compound screening, we found an opioid receptor agonist, namely loperamide hydrochloride (OPA1), most significantly suppressed AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, were then verified in AML cells in vitro, and AML mouse models carrying t(11q23) and t(8;21) in vivo. OPA1-induced activation of OPRM1 enhanced the transcription of TET2, increased DNA 5-hydroxymethylcytosine (5hmC) modification, and in turn, activated NFκB signaling. Notably, AML with TET2 mutations or chemotherapy resistance were sensitive to OPA1. Our results unveiled the previously unappreciated OPRM1-TET2-5hmC-TRAF2 regulatory axis in AML, and highlighted the therapeutic potential of opioid agonists, particularly OPA1, a FDA-approved antidiarrheal drug, in treating AML, especially TET2 mutated AML and chemotherapy-resistant AML, which were known to have poor prognosis.
2023-03-20 | GSE147510 | GEO
Project description:Acute myeloid leukemia (AML) is a type of heterogeneous and fatal hematopoietic malignancy. The ten-eleven translocation (TET) mediated DNA demethylation is known to be critically associated with AML pathogenesis. Through chemical compound screening, we found that the opioid receptor agonist, loperamide hydrochloride (OPA1), significantly suppresses AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, were then verified in AML cells in vitro, and t(11q23) and t(8;21) AML mouse models in vivo. OPA1-induced activation of OPRM1 enhanced the transcription of TET2, increased DNA 5-hydroxymethylcytosine (5hmC) modification, and in turn, activated NFκB signaling. Notably, AML with TET2 mutations or chemotherapy resistance were highly sensitive to OPA1. Our results reveal a previously unknown OPRM1-TET2-5hmC-TRAF2 regulatory axis in AML, and suggest that opioid agonists, particularly OPA1, an FDA-approved antidiarrheal drug, have therapeutic potential in AML, especially in TET2 mutated and chemotherapy-resistant AML, which have a poor prognosis.
2024-01-19 | GSE165650 | GEO
Project description:Agonists for the nociceptin/orphanin FQ opioid peptide NOP receptor, a member of the opioid receptor family, are under active investigation as novel analgesics, but their modes of signaling are less well characterized than those for other members of the opioid receptor family. Therefore, we investigated whether different NOP receptor ligands show differential signaling or functional selectivity at the NOP receptor. Using newly developed phosphosite-specific antibodies to NOP receptor, we found that agonist-induced NOP receptor phosphorylation occurred primarily at four carboxyl-terminal serine (S) and threonine (T) residues, namely Ser346, Ser351, Thr362 and Ser363, and proceeded with a temporal hierarchy, with Ser346 as the first site of phosphorylation. G protein-coupled receptor kinases 2 and 3 (GRK2/3) cooperated during agonist-induced phosphorylation, which in turn facilitated NOP receptor desensitization and internalization. A comparison of structurally distinct NOP receptor agonists revealed dissociation in functional efficacies between G protein-dependent signaling and receptor phosphorylation. Furthermore, in vivo, in NOP-eGFP and NOP-eYFP mice, NOP receptor agonists induced multisite phosphorylation and internalization in a dose-dependent and agonist-selective manner that could be blocked by specific antagonists. Together, our study provides novel tools to study ligand-activated NOP receptor signaling in vitro and in vivo. Differential agonist-selective NOP receptor phosphorylation by chemically diverse NOP receptor agonists suggests that differential signaling by NOP receptor agonists may play a role in NOP receptor ligand pharmacology.
2020-05-26 | PXD012908 | Pride
Project description:Therapy-related acute myeloid leukaemia (t-AML) is a late adverse effect of previous chemotherapy(ct-AML) and/or radiotherapy (rt-AML) or immunosuppressive treatment. t-AMLs represent ~10-20% of all AML cases, are extremely aggressive and have a poor prognosis in comparison to de novo AML. We hypothesised that in rt-AML, exposure to radiation leads to genome-wide epigenetic modifications. An epigenome-wide association study was conducted, measuring over 850K methylation sites across the whole genome in 14 donors. We focused on 94K sites lying in CpG-rich gene promoter regions. Overall, we found genome-wide hypo-methylation in AML and identified specific genes with promoter hyper-methylation. Additionally, pyrosequencing was used to quantify the methylation in 24 samples. We confirmed that the promoters of the genes MEST and GATA5, both previously reported as tumour suppressors, were specifically hyper-methylated in rt-AML in comparison to control and other subtypes of t-AML. These may represent the epigenetic contribution to rt-AML development at the molecular level and be potential drug targets in rt-AML.
2023-01-18 | GSE212937 | GEO
Project description:Due to the current opioid epidemic, a better understanding of genetic and environmental factors that contribute to opioid addiction is warranted. To explore the potential causative role of VitD in opioid addiction , we used multiple pharmacologic approaches and genetic mouse models. We used profiled the transcriptome of key brain reward regions upon morphine treatment in vitamin D receptor KO and wild type mice. Our results highlight the role of VitD deficiency in the development of addiction and suggest a potential therapeutic benefit of VitD supplementation for VitD deficient individuals in the prevention and management of addiction.
2021-04-25 | GSE171683 | GEO
Project description:Opioid abuse poses significant risk to individuals in the United States and epigenetic changes are a leading potential biomarker of opioid abuse. Current evidence, however, is mostly limited to candidate gene analysis in whole blood. Here, we provide Illumina HumanMethylationEPIC array data generated in dorsolateral prefrontal cortex tissue from 153 deceased invidiuals: 72 who died of acute opioid intoxication, 53 psychiatric controls, and 28 normal controls. Using these data, we conducted an epigenome-wide association study and identified one CpG site within a gene (NTN1) that may be related to opioid use. We also detected accelerated PhenoAge in opioid samples compared to control samples.
2021-04-01 | GSE164822 | GEO
Project description:The outcome of Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remain dismal despite the development of treatment. Exploration of alternative targeted gene therapy gradually become a new hot field in improving prognosis. We found BRAF was overexpressed in AML and MDS, which is correlated with poor prognosis. The BRAF inhibitor-Vemurafenib (VEM) could significantly induce senescence and therefore resulted in proliferation inhibition and apoptosis of AML cells. Moreover, this inhibitory effect was verified in CD34+ cells derived from AML patients, and enhanced by Bortezomib (BOR). Mechanistically, we showed that VEM combined with BOR could upregulate MST2 and turned on HIPPO signaling pathway, thereby inducing cellular senescence in vitro and vivo. Our data implicated BRAF expression in the biology of AML patients. We reported clinical correlates and provide a potential biological basis for these correlations. Analyzing the expression of BRAF may help predict prognosis and provide potential therapeutic target for AML and MDS patients.
2023-05-11 | GSE231644 | GEO