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Polyploidization and functional maturation are two distinct processes
during megakaryocytic differentiation: involvement of cyclin-dependent
kinase inhibitor p21 in polyploidization
J Kikuchi, Y Furukawa, S Iwase, Y Terui, M Nakamura, S Kitagawa, M Kitagawa, N Komatsu and Y Miura
Department of Hematology, Jichi Medical School, Kawachi-gun, Tochigi,
Japan.
The mechanism of megakaryocytic differentiation was investigated using
human megakaryocytic leukemia cell line UT-7. Polyploidization of UT-7
cells was induced by the microtubule-depolymerizing agent, nocodazole, and
12-O-tetradecanoylphorbol-13-acetate (TPA), but the effect was much more
striking with nocodazole. By contrast, induction of cytoplasmic maturation,
as judged by beta-thromboglobulin production and platelet factor 4
expression, was more prominent in TPA-treated cells than in
nocodazole-treated cells. Nocodazole and TPA could act synergistically to
increase ploidy and to enhance the expression of mature phenotypes. Human
thrombopoietin induced functional maturation but not polyploidization in
UT-7 cells and also acts synergistically with nocodazole. Cyclin-dependent
kinase inhibitor p21 was upregulated at the early stage of megakaryocytic
differentiation, and overexpression of p21 resulted in an increase in
ploidy of UT-7 cells. This suggests that p21 is implicated in
polyploidization via suppression of CDC2 activity at mitosis. UT-7 but not
HL-60 cells could incorporate [3H]thymidine in the presence of TPA,
indicating the presence of megakaryocyte-specific licensing factor to allow
DNA replication during differentiation. Taking these data together, we
propose that megakaryocytic differentiation consists of two distinct
processes, polyploidization and functional maturation, and that these two
processes are independently regulated.
Volume 89,
Issue 11,
pp. 3980-3990,
06/01/1997
Copyright © 1997 by The American Society of Hematology
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