ETV6/ARG oncoprotein confers autonomous cell growth by enhancing c-Myc expression via signal transducer and activator of transcription 5 activation in the acute promyelocytic leukemia cell line HT93A.
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.
a Division of Hematology and Rheumatology, Department of Medicine , Nihon University School of Medicine , Tokyo , Japan.
Noriyoshi
N
Iriyama
a Division of Hematology and Rheumatology, Department of Medicine , Nihon University School of Medicine , Tokyo , Japan.
Yoshihiro
Y
Hatta
a Division of Hematology and Rheumatology, Department of Medicine , Nihon University School of Medicine , Tokyo , Japan.
Masami
M
Takei
D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D000097764:ETS Translocation Variant 6 Protein
D018797:Cell Cycle Proteins; D016179:Granulocyte Colony-Stimulating Factor; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; D050783:Proto-Oncogene Proteins c-ets; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D000097764:ETS Translocation Variant 6 Protein; C426236:ARG tyrosine kinase; C498826:nilotinib
ETV6/ARG; HT93A; c-Myc; signal transducer and activator of transcription