title: 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.
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: P V
authors.initials: PV
authors.lastname: Spirin
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: T D
authors.initials: TD
authors.lastname: Lebedev
authors.affiliation: 1] Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia [2] Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
authors.forename: N N
authors.initials: NN
authors.lastname: Orlova
authors.affiliation: 1] Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia [2] Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
authors.forename: A S
authors.initials: AS
authors.lastname: Gornostaeva
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: M M
authors.initials: MM
authors.lastname: Prokofjeva
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: N A
authors.initials: NA
authors.lastname: Nikitenko
authors.affiliation: 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.
authors.forename: S E
authors.initials: SE
authors.lastname: Dmitriev
authors.affiliation: 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.
authors.forename: A A
authors.initials: AA
authors.lastname: Buzdin
authors.affiliation: 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.
authors.forename: N M
authors.initials: NM
authors.lastname: Borisov
authors.affiliation: 1] Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia [2] D Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
authors.forename: A M
authors.initials: AM
authors.lastname: Aliper
authors.affiliation: 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.
authors.forename: A V
authors.initials: AV
authors.lastname: Garazha
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: P M
authors.initials: PM
authors.lastname: Rubtsov
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Stocking
authors.affiliation: 1] Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia [2] Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
authors.forename: V S
authors.initials: VS
authors.lastname: Prassolov
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008957:Models, Genetic; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D000075142:RUNX1 Translocation Partner 1 Protein; D019009:Proto-Oncogene Proteins c-kit
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