Targeting of AML1-ETO in t(8;21) leukemia by oridonin generates a tumor suppressor-like protein.

Zhen, Tao, Wu, Chuan-Feng, Liu, Ping, Wu, Hai-Yan, Zhou, Guang-Biao, Lu, Ying, Liu, Jian-Xiang, Liang, Yang, Li, Keqin Kathy, Wang, Yue-Ying, Xie, Yin-Yin, He, Miao-Miao, Cao, Huang-Ming, Zhang, Wei-Na, Chen, Li-Min, Petrie, Kevin, Chen, Sai-Juan and Chen, Zhu (2012) Targeting of AML1-ETO in t(8;21) leukemia by oridonin generates a tumor suppressor-like protein. Science translational medicine, 4 (127). 127ra38. ISSN 1946-6242

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Abstract

Nearly 60% of acute myeloid leukemia (AML) patients with the t(8;21)(q22;q22) translocation fail to achieve long-term disease-free survival. Our previous studies demonstrated that oridonin selectively induces apoptosis of t(8;21) leukemia cells and causes cleavage of AML1-ETO oncoprotein resulting from t(8;21), but the underlying mechanisms remain unclear. We show that oridonin interacted with glutathione and thioredoxin/thioredoxin reductase to increase intracellular reactive oxygen species, which in turn activated caspase-3 in t(8;21) cells. Moreover, oridonin bound AML1-ETO, directing the enzymatic cleavage at aspartic acid 188 via caspase-3 to generate a truncated AML1-ETO (ΔAML1-ETO) and preventing the protein from further proteolysis. ΔAML1-ETO interacted with AML1-ETO and interfered with the trans-regulatory functions of remaining AML1-ETO oncoprotein, thus acting as a tumor suppressor that mediates the anti-leukemia effect of oridonin. Furthermore, oridonin inhibited the activity of c-Kit(+) leukemia-initiating cells. Therefore, oridonin is a potential lead compound for molecular target-based therapy of leukemia.

Item Type: Article
Subjects: Sciences > Biomedical Sciences
Sciences > Health Sciences
Divisions: Faculty of Health Sciences and Wellbeing > School of Medicine
Depositing User: Kevin Petrie
Date Deposited: 18 Aug 2020 18:02
Last Modified: 19 Aug 2020 09:41
URI: http://sure.sunderland.ac.uk/id/eprint/12435
ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

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