Opioid receptor signaling suppresses leukemia through both catalytic and non-catalytic functions of TET2
Acute myeloid leukemia (AML) is a genetically heterogeneous and frequently fatal malignancy. The ten-eleven translocation (TET)-mediated DNA demethylation is known to be critically associated with AML pathogenesis. Through chemical compound screening, we find that the opioid receptor agonist, lopera...
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Published in | Cell reports (Cambridge) Vol. 38; no. 4; p. 110253 |
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Main Authors | , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
25.01.2022
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | Acute myeloid leukemia (AML) is a genetically heterogeneous and frequently fatal malignancy. The ten-eleven translocation (TET)-mediated DNA demethylation is known to be critically associated with AML pathogenesis. Through chemical compound screening, we find that the opioid receptor agonist, loperamide hydrochloride (OPA1), significantly suppresses AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, are verified in AML cells in vitro and mouse and human AML models in vivo. OPA1-induced activation of OPRM1 signaling enhances the transcription of TET2 and thus activates both catalytic-dependent and -independent functions of TET2. Notably, AMLs with TET2 mutations or chemotherapy resistance are sensitive to OPA1 as well. Our results reveal the OPRM1-TET2 regulatory axis in AML and suggest that opioid agonists, particularly OPA1, a US Food and Drug Administration (FDA)-approved antidiarrheal drug, have therapeutic potential in AML, especially in TET2-mutated and chemotherapy-resistant AMLs, which have a poor prognosis.
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•Opioid signaling agonists have therapeutic potential in AML•Opioid signaling activates TET2 transcription and increases global 5hmC level•TET2 enzymatic activity-dependent and -independent functions in OPA1 response•The OPRM1-TET2 regulatory axis is involved in AML
The regulatory pathway of the TET-mediated DNA demethylation remains unclear in acute myeloid leukemia (AML). Zhao et al. report the beneficial therapeutic effects of opioid-receptor agonists, especially loperamide hydrochloride (OPA1) in AML, as OPA1 induces the activation of the OPRM1-TET2 regulatory axis in TET2-mutated and chemotherapy-resistant AML. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2021.110253 |