title: Targeting of AML1-ETO in t(8;21) leukemia by oridonin generates a tumor suppressor-like protein.
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.
authors.affiliation: State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS), Shanghai, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhen
authors.forename: Chuan-Feng
authors.initials: CF
authors.lastname: Wu
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Wu
authors.forename: Guang-Biao
authors.initials: GB
authors.lastname: Zhou
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: Jian-Xiang
authors.initials: JX
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Liang
authors.forename: Keqin Kathy
authors.initials: KK
authors.lastname: Li
authors.forename: Yue-Ying
authors.initials: YY
authors.lastname: Wang
authors.forename: Yin-Yin
authors.initials: YY
authors.lastname: Xie
authors.forename: Miao-Miao
authors.initials: MM
authors.lastname: He
authors.forename: Huang-Ming
authors.initials: HM
authors.lastname: Cao
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Zhang
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Chen
authors.forename: Kevin
authors.initials: K
authors.lastname: Petrie
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics; D055550:Protein Stability / Q000187:drug effects; D000075142:RUNX1 Translocation Partner 1 Protein; D017382:Reactive Oxygen Species / Q000378:metabolism; D014178:Translocation, Genetic / Q000187:drug effects*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D045786:Diterpenes, Kaurane; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; C011959:oridonin; D053148:Caspase 3