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*
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030;
IRSP, Science Applications International Corporation Frederick, and
Division of Basic Sciences, Cytokine Molecular Mechanisms Section, Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD 21702; and
§
Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
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 µM) 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 (Tyr694), and Stat5b (Tyr699); 2) serine
phosphorylation of Stat5a (Ser726) as determined by a novel
phosphospecific Ab; and 3) Stat5a/b DNA binding to the Stat5-responsive
ß-casein promoter. In contrast, AG-490 had no effect on DNA binding
by p50/p65 components of NF-
B, 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.
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