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

Leuk Lymphoma. 2015;56(8):2416-23. doi: 10.3109/10428194.2014.982643. Epub 2014 Dec 4.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / genetics
  • Cell Cycle Proteins / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • ETS Translocation Variant 6 Protein
  • Gene Expression Regulation, Leukemic* / drug effects
  • Granulocyte Colony-Stimulating Factor / pharmacology
  • Humans
  • Leukemia, Promyelocytic, Acute / genetics*
  • Leukemia, Promyelocytic, Acute / metabolism*
  • Leukemia, Promyelocytic, Acute / pathology
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Phosphorylation
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins c-ets / genetics
  • Proto-Oncogene Proteins c-ets / metabolism*
  • Proto-Oncogene Proteins c-myc / genetics*
  • Pyrimidines / pharmacology
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • STAT5 Transcription Factor / metabolism*

Substances

  • Cell Cycle Proteins
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins c-ets
  • Proto-Oncogene Proteins c-myc
  • Pyrimidines
  • Repressor Proteins
  • STAT5 Transcription Factor
  • Granulocyte Colony-Stimulating Factor
  • ARG tyrosine kinase
  • Protein-Tyrosine Kinases
  • nilotinib