| Research Abstract |
The ETV6/TEL gene is a transcription factor, one of the ETS family members. This gene has been reported to fuse to a variety of genes, PDGFRB, MDSl/EVI1, BTL, ACS2, STL, JAK2, ABL, CDX2, TRKC, AML1, MN1, Pax5 and so on. Among them, PDGFRB, ABL, JAK2 and TRKC are tyrosine kinases (TK). We believe that function analysis of ETV6 fusion proteins should contribute much to understanding mechanism of leukemogenesis. We already identified a novel ETV6 partner gene, ARG (ABL related gene or ABL2), another TK gene in a cell line established from an AML-M3 patient with at(15 ; 17)(q22 ; q1 1.2) and at(1 ; 12)(q25 ; p13). We have analysed function of this tyrosine kinase/ETV6 fusion protein, and have demonstrated that this protein confers IL3 independent growth to Ba/F3 cells, and anchorage independent growth activity to Rat- 1 cells, indicating that this protein possesses oncogenic activity similar to the other tyrosine kinase/TETV6 proteins. Further study has shown that the ETV6/ARG oncoprotein
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triggers some of the same signaling pathways associated with activated ABL oncogenes through similar signaling molecules including PI3K, SHC, ras-GAP and CRK-L. Although the ABL is well known to be involved in various human malignancies, ARG has not been reported to be involved in human malignancies despite of its high homology to ABL. Thus, this is the first report showing involvement of ARG in human leukemia, and that ETV6/ARG protein has oncogenic activity.
ETV6/ARG fusion gene has been reported in three types of leukemias (M3, M4eo and T-ALL), so far. In the HT93Acell line established from a M3 patient, unique differentiation to neutrophils, eosinophils and basophils is observed in culture with all-trans retinoic acid and cytokines (IL3, GCSF, GM-CSF). In T-ALL cell line, a surprising differentiation to myeloid cells is observed in culture with cytokines (IL3, G-CSF, and GM-CSF). Taken together, ETV6/ARG protein is likely to possess differentiation capacity under specific condition with some cytokines. Therefore, we started to examine differentiation capacity of ETV6/ARG protein. After transfection of ETV6/ARG constructs to K562 or HL60, we continued to observe change of cell morphology. With full ETV6/ARG construct transfection, cell morphological change has not been observed. Now, we are doing the similar experiment with ETV6 A 5/ARG construct which has deletion of ETV6 ex. 5. Less
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