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  • Title: Targeting of AML1-ETO in t(8;21) leukemia by oridonin generates a tumor suppressor-like protein.
    Author: Zhen T, Wu CF, Liu P, Wu HY, Zhou GB, Lu Y, Liu JX, Liang Y, Li KK, Wang YY, Xie YY, He MM, Cao HM, Zhang WN, Chen LM, Petrie K, Chen SJ, Chen Z.
    Journal: Sci Transl Med; 2012 Mar 28; 4(127):127ra38. PubMed ID: 22461642.
    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.
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