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Leukemia. 2014 Nov;28(11):2222-8. doi: 10.1038/leu.2014.130. Epub 2014 Apr 14.

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

Author information

1
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
2
1] Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia [2] Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
3
1] Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia [2] Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
4
1] Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia [2] D Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia [3] Pathway Pharmaceuticals Limited, Wan Chai, Hong Kong Special Administrative Region.
5
1] D Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia [2] Pathway Pharmaceuticals Limited, Wan Chai, Hong Kong Special Administrative Region.
6
1] Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia [2] D Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
7
Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.

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.

PMID:
24727677
DOI:
10.1038/leu.2014.130
[Indexed for MEDLINE]

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