Leukemia, 2014, 28(11):2222-2228

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

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.

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

IBCH: 4370
Ссылка на статью в журнале: http://www.nature.com/articles/leu2014130
Кол-во цитирований на 11.2020: 41
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