Abstract
We investigated the role of ETV6/ARG fusion gene by exposing the HT93A cell line to nilotinib. HT93A cells were cultured with or without nilotinib±50 ng/mL of granulocyte colony-stimulating factor (G-CSF). Nilotinib treatment inhibited cell growth by increasing the percentage of cells in G0/G1 phase through the decrease of phosphorylated signal transducer and activator of transcription 3 (STAT3) (Y705), STAT5 (Y694) and c-Myc expression. After stimulation with G-CSF, STAT5 but not STAT3 was significantly phosphorylated in both nilotinib-treated and untreated cells. Moreover, combination therapy with nilotinib and G-CSF returned the expression level of c-Myc, cell growth and cell cycle distribution to the control level. These findings suggest that the ETV6/ARG oncoprotein contributes to autonomous cell growth by compensating for the requirement of growth factor through activating STAT5 signaling, which leads to the up-regulation of c-Myc. Our data suggest that ETV6/ARG oncoprotein is a potential target in the treatment of leukemia.
Keywords:
ETV6/ARG; HT93A; c-Myc; signal transducer and activator of transcription.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Cycle Checkpoints / drug effects
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Cell Cycle Checkpoints / genetics
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Cell Cycle Proteins / genetics
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Cell Line, Tumor
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Cell Proliferation / drug effects
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ETS Translocation Variant 6 Protein
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Gene Expression Regulation, Leukemic* / drug effects
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Granulocyte Colony-Stimulating Factor / pharmacology
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Humans
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Leukemia, Promyelocytic, Acute / genetics*
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Leukemia, Promyelocytic, Acute / metabolism*
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Leukemia, Promyelocytic, Acute / pathology
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Phosphorylation
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins c-ets / genetics
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Proto-Oncogene Proteins c-ets / metabolism*
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Proto-Oncogene Proteins c-myc / genetics*
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Pyrimidines / pharmacology
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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STAT5 Transcription Factor / metabolism*
Substances
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Cell Cycle Proteins
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Oncogene Proteins, Fusion
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Proto-Oncogene Proteins c-ets
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Proto-Oncogene Proteins c-myc
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Pyrimidines
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Repressor Proteins
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STAT5 Transcription Factor
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Granulocyte Colony-Stimulating Factor
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ARG tyrosine kinase
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Protein-Tyrosine Kinases
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nilotinib