Journal
ONCOTARGET
Volume 8, Issue 34, Pages 56991-57002Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.18503
Keywords
acute myeloid leukemia; signaling pathways; RUNX1-ETO; ERK2-inhibitors
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Funding
- Russian Science Foundation [14-50-00060, 14-14-01089-Pi]
- Russian Science Foundation [14-50-00060, 17-14-00101] Funding Source: Russian Science Foundation
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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.
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