Functional Uncoupling of the Janus Kinase 3-Stat5 Pathway in Malignant Growth of Human T Cell Leukemia Virus Type 1-Transformed Human T Cells

• Published in: The Journal of immunology (1950) 2000-11, Vol.165 (9), p.5097-5104
• Main Authors: Kirken, Robert A, Erwin, Rebecca A, Wang, Lihua, Wang, Yuling, Rui, Hallgeir, Farrar, William L
• Format: Article
• Language: English
• Subjects: Cell Line, Transformed; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - immunology; Cell Transformation, Neoplastic - pathology; Cell Transformation, Viral - immunology; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - isolation & purification; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Enzyme Inhibitors - pharmacology; Growth Inhibitors - pharmacology; Human T-lymphotropic virus 1 - immunology; Humans; Immunosuppressive Agents - pharmacology; Interleukin-15 - antagonists & inhibitors; Interleukin-15 - pharmacology; Interleukin-2 - antagonists & inhibitors; Interleukin-2 - pharmacology; Jak3 kinase; Janus Kinase 3; Lymphocyte Activation - drug effects; Milk Proteins; NF-kappa B - metabolism; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - metabolism; Phosphorylation - drug effects; Phytohemagglutinins - antagonists & inhibitors; Phytohemagglutinins - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - isolation & purification; Protein-Tyrosine Kinases - metabolism; Protein-Tyrosine Kinases - physiology; Serine - antagonists & inhibitors; Serine - metabolism; Signal Transduction - drug effects; Signal Transduction - immunology; STAT5 Transcription Factor; Stat5a protein; Stat5b protein; T-Lymphocytes - drug effects; T-Lymphocytes - enzymology; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Trans-Activators - antagonists & inhibitors; Trans-Activators - isolation & purification; Trans-Activators - metabolism; Trans-Activators - physiology; Tumor Cells, Cultured; Tumor Suppressor Proteins; Tyrosine - antagonists & inhibitors; Tyrosine - metabolism; Tyrphostins - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.9.5097

Human T cell leukemia virus type 1 (HTLV-1) transforms cytokine-dependent T lymphocytes and causes adult T cell leukemia. Janus tyrosine kinase (Jak)3 and transcription factors Stat5a and Stat5b are essential for the proliferation of normal T cells and are constitutively hyperactivated in both HTLV-1-transformed human T cell lines and lymphocytes isolated from HTLV-1-infected patients; therefore, a critical role for the Jak3-Stat5 pathway in the progression of this disease has been postulated. We recently reported that tyrphostin AG-490 selectively blocked IL-2 activation of Jak3/Stat5 and growth of murine T cell lines. Here we demonstrate that disruption of Jak3/Stat5a/b signaling with AG-490 (50 microM) blocked the proliferation of primary human T lymphocytes, but paradoxically failed to inhibit the proliferation of HTLV-1-transformed human T cell lines, HuT-102 and MT-2. Structural homologues of AG-490 also inhibited the proliferation of primary human T cells, but not HTLV-1-infected cells. Disruption of constitutive Jak3/Stat5 activation by AG-490 was demonstrated by inhibition of 1) tyrosine phosphorylation of Jak3, Stat5a (Tyr(694)), and Stat5b (Tyr(699)); 2) serine phosphorylation of Stat5a (Ser(726)) as determined by a novel phosphospecific Ab; and 3) Stat5a/b DNA binding to the Stat5-responsive beta-casein promoter. In contrast, AG-490 had no effect on DNA binding by p50/p65 components of NF-kappaB, a transcription factor activated by the HTLV-1-encoded phosphoprotein, Tax. Collectively, these data suggest that the Jak3-Stat5 pathway in HTLV-1-transformed T cells has become functionally redundant for proliferation. Reversal of this functional uncoupling may be required before Jak3/Stat5 inhibitors will be useful in the treatment of this malignancy.