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Wilms' Tumor Gene (WT1) Competes With Differentiation-Inducing
Signal in Hematopoietic Progenitor Cells
Kazushi Inoue,
Hiroya Tamaki,
Hiroyasu Ogawa,
Yoshihiro Oka,
Toshihiro Soma,
Toyoshi Tatekawa,
Yusuke Oji,
Akihiro Tsuboi,
Eui
Ho Kim,
Manabu Kawakami,
Tetsu Akiyama,
Tadamitsu Kishimoto, and
Haruo Sugiyama
From the Departments of Medicine III and of Clinical Laboratory
Science, Osaka University Medical School, Osaka, Japan; and The
Research Institute for Microbial Diseases, Osaka University, Osaka,
Japan.
The WT1 gene is a tumor-suppressor gene that was isolated as a gene
responsible for Wilms' tumor, a childhood kidney neoplasm. We have
previously reported that the WT1 gene is strongly expressed in leukemia
cells with an increase in its expression levels at relapse and an
inverse correlation between its expression levels and prognosis, thus
making it a novel tumor marker for leukemic blast cells. Furthermore,
WT1 antisense oligomers have been found to inhibit the growth of
leukemic cells. These results strongly suggested the involvement of the
WT1 gene in human leukemogenesis. The present study was performed to
prove our hypothesis that the WT1 gene plays a key role in
leukemogenesis and performs an oncogenic function in hematopoietic
progenitor cells, rather than a tumor-suppressor gene function. 32D
cl3, an interleukin-3-dependent myeloid progenitor cell line,
differentiates into mature neutrophils in response to granulocyte
colony-stimulating factor (G-CSF). However, when transfected wild-type
WT1 gene was constitutively expressed in 32D cl3, the cells stopped
differentiating and continued to proliferate in response to G-CSF. As
for signal transduction mediated by G-CSF receptor (G-CSFR), Stat3
was constitutively activated in wild-type WT1-infected 32D cl3 in
response to G-CSF, whereas, in WT1-uninfected 32D cl3, activation of
Stat3 was only transient. However, most interesting was the fact
that G-CSF stimulation resulted in constitutive activation of Stat3
only in wild-type WT1-infected 32D cl3, but not in WT1-uninfected 32D
cl3. Thus, WT1 expression constitutively activated both Stat3 and
Stat3. A transient activation of Stat1 was detected in both
wild-type WT1-infected and uninfected 32D cl3 after G-CSF stimulation,
but no difference in its activation was found. No activation of MAP
kinase was detected in both wild-type WT1-infected and uninfected 32D
cl3 after G-CSF stimulation. These results demonstrated that WT1
expression competed with the differentiation-inducing signal mediated
by G-CSFR and constitutively activated Stat3, resulting in the blocking
of differentiation and subsequent proliferation. Therefore, the data
presented here support our hypothesis that the WT1 gene plays an
essential role in leukemogenesis and performs an oncogenic function in
hematopoietic progenitor cells and represent the first demonstration of
an important role of the WT1 gene in signal transduction in
hematopoietic progenitor cells.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2969-2976
© 1998 by The American Society of Hematology.
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