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Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3765-3770
Constitutive Stat3, Tyr705, and Ser727 phosphorylation in acute
myeloid leukemia cells caused by the autocrine secretion of
interleukin-6
Jan-Jacob Schuringa,
Albertus T. J. Wierenga,
Wiebe Kruijer, and
Edo Vellenga
From the Department of Hematology, University Hospital Groningen,
Groningen, and the Department of Genetics, Biological Center, Kerklaan,
Haren, The Netherlands.
To explore the activation patterns of signal transducer and
activator of transcription 3 (Stat3) in acute myeloid leukemia (AML),
we examined whether the phosphorylation of tyrosine705 (Tyr705) and
serine727 (Ser727) residues was abnormally regulated in cells from
patients with AML. In 5 of 20 (25%) patients with AML, Stat3 was
constitutively phosphorylated on Tyr705 and Ser727, which were not
further up-regulated by treatment with IL-6. Furthermore, Stat3 was
constitutively bound to the IRE response element in these cells as
determined by electrophoretic mobility shift assay, and stimulation
with IL-6 did not result in increased DNA binding. Interestingly, AML
cells with constitutive Stat3 activation also secreted high levels of
IL-6 protein. Treating these AML cells with anti-IL-6 resulted in
restored IL-6-inducible Stat3 phosphorylation on both Tyr705 and
Ser727 with low or undetectable basal phosphorylation levels in
unstimulated cells. In contrast, treatment with anti-IL-1 did not
result in altered Stat3 phosphorylation patterns. The constitutive IL-6
expression was associated with elevated levels of suppressor of
cytokine signaling-1 (SOCS-1) and SOCS-3 mRNA expression, which were
not down-regulated by anti-IL-6. These data indicate that the
constitutive Stat3 activation in the investigated AML blasts is caused
by high IL-6 secretion levels, thus stimulating the Jak/Stat pathway in
an autocrine manner, a paracrine manner, or both.
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