Transformation of Ba/F3 cells and Rat-1 cells by ETV6/ARG.
ETV6/ARG, a novel fusion gene composed of the ETV6 HLH oligomerization domain and most of sequences of the ARG protein tyrosine, was recently identified in human leukemia cells. The presence of the ETV6/ARG translocation raises the possibility that the resulting fusion protein functions as an oncogene. However, the transforming activity of the ETV6/ARG protein has not been determined and its contribution to leukemogenesis is therefore unknown. Here we address this question by analysing the oncogenic activity of ETV6/ARG in hematopoietic and fibroblast cells. It is demonstrated that expression of ETV6/ARG confers IL3-independent growth to Ba/F3 cells and anchorage independent growth to Rat-1 fibroblasts. It is also shown that multiple signaling molecules, including PI3K, SHC, ras-GAP and CRK-L, are tyrosine phosphorylated in Ba/F3 cells that express ETV6/ARG. Analysis of four different types of ETV6/ARG transcripts previously identified in the AML-M3 leukemia cell line HT93A suggest that ETV6 HLH domain is required for oncogenic activity. Based upon these results it is concluded that ARG can be activated as an oncogene in human malignancy and that the ETV6/ARG oncoprotein triggers some of the same signaling pathways associated with activated ABL oncogenes.
Iijima
Yoshimi
Y
Division of Molecular Cytogenetics, Department of Clinical Pathology, Research Institute, International Medical Center of Japan, Tokyo 162-0052, Japan.
Okuda
Keiko
K
Tojo
Arinobu
A
Tri
Nguyen Khanh
NK
Setoyama
Misao
M
Sakaki
Yoshiyuki
Y
Asano
Shigetaka
S
Tokunaga
Katsushi
K
Kruh
Gary D
GD
Sato
Yuko
Y
D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics; D016313:Genes, abl / Q000502:physiology; D006801:Humans; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D010957:Plasmids; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012097:Repressor Proteins / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D000097764:ETS Translocation Variant 6 Protein
D004268:DNA-Binding Proteins; D016044:Fusion Proteins, bcr-abl; D007377:Interleukin-3; D015513:Oncogene Proteins; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D050783:Proto-Oncogene Proteins c-ets; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014443:Tyrosine; D000097764:ETS Translocation Variant 6 Protein; C426236:ARG tyrosine kinase