Silencing AML1-ETO gene expression leads to simultaneous activation of both pro-apoptotic and proliferation signaling.

Spirin PV; Lebedev TD; Orlova NN; Gornostaeva AS; Prokofjeva MM; Nikitenko NA; Dmitriev SE; Buzdin AA; Borisov NM; Aliper AM; Garazha AV; Rubtsov PM; Stocking C; Prassolov VS

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Article

Title:	Silencing AML1-ETO gene expression leads to simultaneous activation of both pro-apoptotic and proliferation signaling.
Authors:	Spirin PV; Lebedev TD; Orlova NN; Gornostaeva AS; Prokofjeva MM; Nikitenko NA; Dmitriev SE; Buzdin AA; Borisov NM; Aliper AM; Garazha AV; Rubtsov PM; Stocking C; Prassolov VS
Publication:	Leukemia. 2014 Nov;28(11):2222-8. doi: 10.1038/leu.2014.130. Epub 2014 Apr 14.
PubmedID	24727677
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.