The TEL/ARG leukemia oncogene promotes viability and hyperresponsiveness to hematopoietic growth factors.
The TEL/ARG oncogene associated with acute myeloid leukemia is formed by the t(1;12)(q25;p13) reciprocal translocation, which fuses part of the TEL gene to the tyrosine kinase, c-ARG. In an effort to determine the biological effects and investigate signaling of the TEL/ARG fusion protein, multiple sublines of Ba/F3 cells were generated in which a TEL/ARG complementary DNA was expressed under the control of a tetracycline-inducible promoter. Treatment of these cells with doxycycline, a tetracycline analogue, rapidly induced expression of the TEL/ARG protein. TEL/ARG was heavily phosphorylated on tyrosine residues and was also found to rapidly induce tyrosine phosphorylation of multiple cellular proteins, including rasGAP, CBL, STAT5, PI3K, SHP2, Dok, and SHC. The Ba/F3-tet-TEL/ARG cells remained interleukin (IL)-3 dependent without doxycycline but with doxycycline displayed a marked reduction in cell death in the absence of IL-3. TEL/ ARG cells also displayed an enhanced proliferative response to IL-3 and to insulin-like growth factor 1. At least in Ba/F3 cells, although the growth rate was much lower compared to that with IL-3, TEL/ARG appeared to induce some cell proliferation as an immediate consequence. Nonetheless, the hyperresponsiveness to growth factors reported here is more likely to contribute to the pathogenesis of leukemia.
Okuda
Keiko
K
Department of Health Sciences and Preventive Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. keiko_o@koto.kpu-m.ac.jp
Sato
Yuko
Y
Sonoda
Yoshiaki
Y
Griffin
James D
JD
D000818:Animals; D000900:Anti-Bacterial Agents; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D004318:Doxycycline; D015870:Gene Expression / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D013379:Substrate Specificity; D014443:Tyrosine / Q000378:metabolism
D000900:Anti-Bacterial Agents; D018076:DNA, Complementary; D007377:Interleukin-3; D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins; C426235:TEL-ARG fusion protein, human; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D011505:Protein-Tyrosine Kinases; D004318:Doxycycline