Opioid receptor signaling suppresses leukemia through both catalytic and non-catalytic functions of TET2.

Abstract

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.

• Authors: Huanhuan Zhao, Jun Lu, Tong Yan, Fei Han, Jie Sun, Xiaolin Yin, Liting Chen, Chao Shen, Mark Wunderlich, Weina Yun, Lingling Yang, Liyun Chen, Dan Su, Stefan K Bohlander, Fudi Wang, James C Mulloy, Chong Li, Jianjun Chen, He Huang, Xi Jiang
• Journal: Cell reports (Cell Rep) Vol. 38 Issue 4 Pg. 110253 (01 25 2022) ISSN: 2211-1247 [Electronic] United States
• PMID: 35081358 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Analgesics, Opioid
• DNA-Binding Proteins
• Receptors, Opioid, mu
• Loperamide
• Dioxygenases
• TET2 protein, human
• Tet2 protein, mouse

Topics

• Analgesics, Opioid (pharmacology)
• Animals
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• DNA-Binding Proteins (metabolism)
• Dioxygenases (metabolism)
• Female
• Humans
• Leukemia, Myeloid, Acute (metabolism, pathology)
• Loperamide (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Receptors, Opioid, mu (drug effects, metabolism)
• Signal Transduction (drug effects, physiology)
• Xenograft Model Antitumor Assays