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- Title
Silencing AML1-ETO gene expression leads to simultaneous activation of both pro-apoptotic and proliferation signaling.
- Authors
Spirin, P V; Lebedev, T D; Orlova, N N; Gornostaeva, A S; Prokofjeva, M M; Nikitenko, N A; Dmitriev, S E; Buzdin, A A; Borisov, N M; Aliper, A M; Garazha, A V; Rubtsov, P M; Stocking, C; Prassolov, V S
- Abstract
The t(8;21)(q22;q22) rearrangement represents the most common chromosomal translocation in acute myeloid leukemia (AML). It results in a transcript encoding for the fusion protein AML1-ETO (AE) with transcription factor activity. AE is considered to be an attractive target for treating t(8;21) leukemia. However, AE expression alone is insufficient to cause transformation, and thus the potential of such therapy remains unclear. Several genes are deregulated in AML cells, including KIT that encodes a tyrosine kinase receptor. Here, we show that AML cells transduced with short hairpin RNA vector targeting AE mRNAs have a dramatic decrease in growth rate that is caused by induction of apoptosis and deregulation of the cell cycle. A reduction in KIT mRNA levels was also observed in AE-silenced cells, but silencing KIT expression reduced cell growth but did not induce apoptosis. Transcription profiling of cells that escape cell death revealed activation of a number of signaling pathways involved in cell survival and proliferation. In particular, we find that the extracellular signal-regulated kinase 2 (ERK2; also known as mitogen-activated protein kinase 1 (MAPK1)) protein could mediate activation of 23 out of 29 (79%) of these upregulated pathways and thus may be regarded as the key player in establishing the t(8;21)-positive leukemic cells resistant to AE suppression.
- Publication
Leukemia (08876924), 2014, Vol 28, Issue 11, p2222
- ISSN
0887-6924
- Publication type
journal article
- DOI
10.1038/leu.2014.130