Synergistic suppression of t(8;21)-positive leukemia cell growth by combining oridonin and MAPK1/ERK2 inhibitors

// Pavel Spirin 1, * , Timofey Lebedev 1, * , Natalia Orlova 1, * , Alexey Morozov 1 , Nadezhda Poymenova 1 , Sergey E. Dmitriev 1, 2 , Anton Buzdin 1, 3, 4 , Carol Stocking 5 , Olga Kovalchuk 6, 7 and Vladimir Prassolov 1 1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia 2 Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia 3 Dmitry Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117997, Russia 4 National Research Centre “Kurchatov Institute”, Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow 123182, Russia 5 Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany 6 OncoFinder Ltd, Lethbridge, AB T1K7X8, Canada 7 Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K3M4, Canada * These authors have contributed equally to this work Correspondence to: Pavel Spirin, email: spirin.pvl@gmail.com Keywords: acute myeloid leukemia, signaling pathways, RUNX1-ETO, ERK2-inhibitors Received: September 16, 2016 Accepted: April 18, 2017 Published: June 16, 2017 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.