Abstract
One of the most common chromosomal translocations in acute myeloid leukemia is t(8;21)(q22;q22), which results in the appearance of abnormal transcripts encoding for the fusion protein RUNX1-ETO. Therefore, this oncoprotein is considered to be a pertinent and promising target for treating t(8;21) leukemia. Previously, we have shown that downregulation of RUNX1-ETO leads to activation of intracellular signaling pathways enhancing cell survival and determined that the protein ERK2 can mediate activation of most of these pathways. Here we used a combination of oridonin (natural tetracycline diterpenoid), which has been shown to exhibit anti-RUNX1-ETO activity, and ERK2 kinase inhibitors. We found that treatment of leukemic t(8;21)-positive Kasumi-1 cells with oridonin cause decrease of phosphorylated ERK1/2. Treatment of these cells with ERK2 inhibitors makes them more sensitive to RUNX1-ETO inhibition with oridonin. Therefore we postulate that simultaneous inhibition of RUNX1-ETO and ERK2 cause synergistic effect on survival of leukemic cells.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic progenitor cells
Selective suppression of RE leads to a www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget widespread reversal of epigenetic reprogramming and a genome-wide redistribution of RUNX1 binding that results in the inhibition of AML cell proliferation, selfrenewal and the induction of differentiation [12]
We identified that the protein ERK2 (MAPK1), one of the regulators responsible for normal and tumor www.impactjournals.com/oncotarget cell proliferation [18, 19], can mediate activation of 79% of these pathways in viable RE-inhibited cells, as shown by the deep molecular pathway analysis using the OncoFinder method [20, 21]
Summary
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic progenitor cells. RE affects normal RUNX1-dependent transcriptional activation through various dominant-negative mechanisms [3,4,5]. It leads to the suppression of a number of RUNX1 target genes and disruption of mechanisms responsible for normal differentiation of hematopoietic stem cells, such as upregulation of COX/β-catenin signaling pathway, abnormal c-jun pathway activation, and C-KIT pathway hyperactivation [4, 9,10,11]. Selective suppression of RE leads to a www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget widespread reversal of epigenetic reprogramming and a genome-wide redistribution of RUNX1 binding that results in the inhibition of AML cell proliferation, selfrenewal and the induction of differentiation [12]
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