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

Cell Reports

Jianjun Chen¹  Xiaolin Yin¹  Weina Yun¹  Tong Yan¹  Mark Wunderlich²  Chong Li²  Jie Sun²  Jun Lu²  Xi Jiang²  Lingling Yang³  James C. Mulloy⁴  Liyun Chen⁴  Huanhuan Zhao⁴  Chao Shen⁴  Fei Han⁴  He Huang⁴  Stefan K. Bohlander⁵  Fudi Wang⁶  Dan Su⁷  Liting Chen⁷ 

[1] Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang 310003, China;Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, Zhejiang 311121, China;Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China;Department of Pharmacology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China;Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA;Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA;Key Laboratory of Luminescence and Real-time Analytical Chemistry (Ministry of Education), College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China;

关键词: acute myeloid leukemia;    AML;    opioid signaling;    targeted therapy;    TET;    5hmC;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown