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Aphidicolin, an inhibitor of DNA replication, blocks the TPA-induced
differentiation of a human megakaryoblastic cell line, MEG-O1
T Murate, T Hotta, K Tsushita, M Suzuki, T Yoshida, S Saga, H Saito and S Yoshida
First Department of Internal Medicine, Nagoya University School of
Medicine, Japan.
The commitment process of a human megakaryoblastic cell line (MEG-O1)
induced with phorbol ester, TPA, was investigated with special reference to
glycoprotein (GP) IIb/IIIa expression, multinuclear formation, and DNA
replication. TPA (10(-7) mol/L) completely inhibited cellular division in
MEG-O1, but did not suppress de novo DNA synthesis. Two days' culture with
10(-7) mol/L TPA was sufficient for MEG-O1 cells to initiate an
irreversible commitment process. These cells could not resume cell growth
and expressed GP IIb/IIIa antigen; some of them showed multinuclear form
and DNA polyploidy even after removal of TPA from the culture medium. DNA
histogram analysis showed that, upon treatment with TPA, the percentage of
cells whose DNA ploidy was more than 8N was 5 to 10 times higher than that
of control cells. Precise analysis using cell size fractionation by
centrifugal elutriation method showed that there was strong correlation
between the percentage of multinuclear cells and DNA polyploidy in
TPA-treated cells. The percentage and staining intensity of GP IIb/IIIa and
other megakaryocytic phenotypes such as von Willebrand factor and PAS
staining were highest in large multinuclear cell populations, suggesting
that these cells are the most differentiated population in this system. In
TPA-treated cells, the activity of DNA polymerase alpha, a marker for cell
growth, remained at the same level as in control cells. Aphidicolin, a
specific inhibitor of DNA polymerase alpha, completely inhibited the
differentiation induction of MEG-O1 cells with TPA measured by either GP
IIb/IIIa expression or multinuclear cell formation. Therefore, DNA
replication appears to be involved in the process of phenotypic expression
as well as endomitosis in megakaryocyte differentiation of MEG-O1 cells.
Aphidicolin was also effective in inhibiting megakaryocytic differentiation
of other leukemia cell lines such as human erythroleukemia (HEL) and K562
cell lines induced with TPA, suggesting the close interplay of DNA
replication and phenotypic expression in megakaryopoiesis.
Volume 78,
Issue 12,
pp. 3168-3177,
12/15/1991
Copyright © 1991 by The American Society of Hematology
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