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Blood, 1 May 2002, Vol. 99, No. 9, pp. 3220-3227
HEMATOPOIESIS
A functional role of Stat3 in in vivo megakaryopoiesis
Keita Kirito,
Masatake Osawa,
Haruhiko Morita,
Ritsuko Shimizu,
Masayuki Yamamoto,
Atsushi Oda,
Hiroyoshi Fujita,
Masaru Tanaka,
Koichi Nakajima,
Yasusada Miura,
Keiya Ozawa, and
Norio Komatsu
From the Division of Hematology, Department of
Medicine, Jichi Medical School, Tochigi; Pharmaceutical Development
Laboratory, Kirin Brewery, Gunma; Center for Tsukuba Advanced Research
Alliance and Institute of Basic Medical Sciences, University of
Tsukuba; Department of Molecular Oncology, Biomedical Research Center,
Osaka University Medical School; and Laboratory of Environmental
Biology, Hokkaido University School of Medicine, Sapporo, Japan.
The signal transducer and activator of transcription 3 (Stat3), a member of the Stat family of proteins, is commonly activated by thrombopoietic cytokines including thrombopoietin (TPO), interleukin (IL)-6, and interleukin-11. This finding strongly suggested that Stat3
has an important role in megakaryopoiesis and thrombopoiesis. To
clarify the functional role of Stat3 in in vivo megakaryopoiesis and
thrombopoiesis, we generated transgenic mice overexpressing a
dominant-negative Stat3, Stat3F, to suppress the function of endogenous
Stat3. To accomplish the selective expression of Stat3F in
megakaryocytic lineage cells, we used the regulatory gene region of
GATA-1 transcription factor selectively expressed in megakaryocytic and
erythroid lineage cells. Two independent transgenic (Tg) mice lines
were established. It was confirmed by Western blotting analysis that
Stat3F proteins were highly expressed in the platelets from the Tg
mice. In addition, it was found that Stat3 activation induced by TPO
stimulation was drastically suppressed in these Tg mice compared with
littermates. These findings indicate that Stat3F works well in the Tg
mice. Platelet counts were within the normal range in steady-state
conditions and were recovered normally from transient thrombocytopenia
induced by antiplatelet serum injection. Interestingly, the platelet
recovery from myelosuppression after 5-fluorouracil treatment was
significantly delayed in the Tg mice. Collectively, our results
strongly suggest that Stat3 plays an important role in the early stage
of megakaryopoiesis, presumably through the expansion of
megakaryocytic progenitor cells.
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