期刊
CELL REPORTS
卷 38, 期 4, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.110253
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资金
- National Natural Science Foundation of China [31900426, 81970144]
- Fundamental Research Funds for the Central Universities
- National Key Research and Development Program of China [2018YFA0507802]
- family of Mar-ijana Kumerich
- Leukaemia and Blood Cancer New Zealand
Researchers have discovered that the opioid receptor agonist OPA1 can suppress the viability of AML cells, especially in TET2-mutated and chemotherapy-resistant cases.
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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