Oridonin-Generated Cleavage Fragment of AML1-ETO Inhibits Its Oligomerization and Oncogenic Function Leading to Differentiation and Apoptosis of Leukemic Cells.

Abstract 1051

Poster Board I-73

Oligomerization through the NHR2 domain is essential for AML1-ETO's inhibition of granulocytic differentiation and enhanced clonogenic potential of primary bone marrow cells. We show here that Oridonin interferes with AML1-ETO oligomerization through its cleavage fragment DAML1-ETO, which consists of the amino acids (aa) 188-752 of the parental oncoprotein or aa 40-604s of the wild-type ETO. DAML1-ETO interacts with the parental AML1-ETO through NHR2 and exerts dominant negative effects on AML1-ETO with regard to DNA binding, transregulatory activity on target genes and regulation of leukemic cell survival, differentiation and proliferation both in vitro and in vivo. Moreover, Oridonin can activate retinoic acid and cAMP/PKA pathways, and potentiate differentiation induced by all-trans retinoic acid (ATRA) and G-CSF. Consistently, combined use of Oridonin, ATRA and G-CSF significantly prolongs lifespan of t (8;21) leukemic mice and, interestingly, we find that this treatment targets the Lin-/Sca-1+/C-KIT+ and Lin-/Sca-1-/C-KIT+ leukemia initiating cells. These data suggest that Oridonin, and potentially other small molecules, can inhibit AML1-ETO oligomerization and leukemogenic function, thus providing a targeted therapy that activates key regulatory pathways for myelomonocytic cell differentiation and apoptosis.