Cell Reports (Jan 2022)
Opioid receptor signaling suppresses leukemia through both catalytic and non-catalytic functions of TET2
- 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
Affiliations
- Huanhuan Zhao
- Department of Pharmacology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, Zhejiang 311121, China; Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang 310003, China
- Jun Lu
- Department of Pharmacology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, Zhejiang 311121, China; Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang 310003, China
- Tong Yan
- Key Laboratory of Luminescence and Real-time Analytical Chemistry (Ministry of Education), College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
- Fei Han
- Department of Pharmacology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, Zhejiang 311121, China; Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang 310003, China
- Jie Sun
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Xiaolin Yin
- Department of Pharmacology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Liting Chen
- Key Laboratory of Luminescence and Real-time Analytical Chemistry (Ministry of Education), College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
- Chao Shen
- Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA
- Mark Wunderlich
- Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
- Weina Yun
- Department of Pharmacology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, Zhejiang 311121, China; Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang 310003, China
- Lingling Yang
- Department of Pharmacology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, Zhejiang 311121, China; Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang 310003, China
- Liyun Chen
- Department of Nutrition, School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Dan Su
- Department of Pharmacology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Stefan K. Bohlander
- Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1142, New Zealand
- Fudi Wang
- Department of Nutrition, School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- James C. Mulloy
- Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
- Chong Li
- Key Laboratory of Luminescence and Real-time Analytical Chemistry (Ministry of Education), College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
- Jianjun Chen
- Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA
- He Huang
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, Zhejiang 311121, China; Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang 310003, China
- Xi Jiang
- Department of Pharmacology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, Zhejiang 311121, China; Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang 310003, China; Corresponding author
- Journal volume & issue
-
Vol. 38,
no. 4
p. 110253
Abstract
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.
