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

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.

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Acknowledgements

This work was supported by the Programs of the Presidium of the Russian Academy of Sciences: ‘Molecular and Cell Biology’, ‘Fundamental Research Basics in Nanotechnology and Nanomaterials’, ‘Dynamics and Conservation of Genomes’ and the Russian Foundation for Basic Research (grant nos. 13-04-00599-a, 14-04-00821-a, 14-04-32108, 12-0433094 and 10-04-00593-a). We thank ‘UMA Foundation’ for their support in preparation of the manuscript.

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Correspondence to V S Prassolov.

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Spirin, P., Lebedev, T., Orlova, N. et al. Silencing AML1-ETO gene expression leads to simultaneous activation of both pro-apoptotic and proliferation signaling. Leukemia 28, 2222–2228 (2014). https://doi.org/10.1038/leu.2014.130

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