ENAGenomicsZhejiang Universityhttps://www.ebi.ac.uk/ena/browser/view/PRJNA697941Homo sapiensAcute 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. Overall design: Bisulphite converted DNA from the 2 samples were hybridised to the Illumina Infinium 850k Human MethylationEPIC BeadChip.ENAleukemia, Tet, Narcotic, Leucocythemia, Enkephalin, beta-Endorphin Receptor, DNA Demethylations, Opiate Receptors, Opioid Receptor, Enkephalin Receptors, Demethylation, Receptors, Narcotic Receptors, Leucocythemias, Opioid Receptors, Enkephalin Receptor, thymoma, Leukemias, Normorphine, Opiate, Endorphin Receptor, Opioid, signalling process, Demethylations, DNA demethylation, Opiate Receptor, Endorphin Receptors, leukaemia NOS, beta-Endorphin, Receptor, Leucocythaemia, DNA, DNA., Normorphine Receptors, beta-Endorphin Receptors, leukaemia, Endorphin, adult, beta Endorphin Receptor, single organism signaling, Leucocythaemias, beta Endorphinleukemia, Tet, Narcotic, Leucocythemia, Enkephalin, beta-Endorphin Receptor, DNA Demethylations, Opiate Receptors, Opioid Receptor, Enkephalin Receptors, Demethylation, Receptors, Narcotic Receptors, Leucocythemias, Opioid Receptors, Enkephalin Receptor, thymoma, Leukemias, Normorphine, Opiate, Endorphin Receptor, Opioid, signalling process, Demethylations, DNA demethylation, Opiate Receptor, Endorphin Receptors, leukaemia NOS, beta-Endorphin, Receptor, Leucocythaemia, DNA, DNA., Normorphine Receptors, beta-Endorphin Receptors, leukaemia, Endorphin, adult, beta Endorphin Receptor, single organism signaling, Leucocythaemias, beta EndorphinfalseOpioid receptor signaling suppresses leukemia by inducing TET-dependent DNA demethylationOpioid receptor signaling suppresses leukemia by inducing TET-dependent DNA demethylation2025-09-242024-01-26PRJNA697941GSE1658039606