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

Sci Transl Med. 2012 Mar 28;4(127):127ra38. doi: 10.1126/scitranslmed.3003562.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 3 / metabolism
  • Chromosomes, Human, Pair 21 / genetics*
  • Chromosomes, Human, Pair 8 / genetics*
  • Core Binding Factor Alpha 2 Subunit / antagonists & inhibitors*
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Diterpenes, Kaurane / pharmacology*
  • Enzyme Activation / drug effects
  • Humans
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Leukemia, Myeloid, Acute / enzymology
  • Leukemia, Myeloid, Acute / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Molecular Targeted Therapy
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology
  • Oncogene Proteins, Fusion / antagonists & inhibitors*
  • Oncogene Proteins, Fusion / genetics
  • Protein Stability / drug effects
  • RUNX1 Translocation Partner 1 Protein
  • Reactive Oxygen Species / metabolism
  • Translocation, Genetic / drug effects*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • AML1-ETO fusion protein, human
  • Core Binding Factor Alpha 2 Subunit
  • Diterpenes, Kaurane
  • Oncogene Proteins, Fusion
  • RUNX1 Translocation Partner 1 Protein
  • Reactive Oxygen Species
  • Tumor Suppressor Proteins
  • oridonin
  • Caspase 3