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Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1568-1577
Phosphatidylinositol 3-Kinase Is Involved in the Protection of Primary
Cultured Human Erythroid Precursor Cells From Apoptosis
Yoshihito Haseyama,
Ken-ichi Sawada,
Atsushi Oda,
Kazuki Koizumi,
Hina Takano,
Takashi Tarumi,
Mitsufumi Nishio,
Makoto Handa,
Yasuo Ikeda, and
Takao Koike
From the Department of Internal Medicine II,
Hokkaido University School of Medicine, Sapporo; and the
Division of Hematology, Department of Internal
Medicine, and the Blood Center, Keio University,
Tokyo, Japan.
Little is known about the physiologic role of phosphatidylinositol
3-kinase (PI-3K) in the development of erythrocytes. Previous studies
have shown that the effects of the PI-3K inhibitor wortmannin on
erythropoietin (EPO)-dependent cell lines differed depending on the
cell type used. Wortmannin inhibited EPO-induced differentiation of
some cell lines without affecting their proliferation; however, the
EPO-induced proliferation of other cell lines was inhibited by
wortmannin. In neither case were signs of apoptosis observed. We have
previously reported that signaling in highly purified human colony
forming units-erythroid (CFU-E), generated in vitro from
CD34+ cells, differed from that in EPO-dependent cell
lines. In the current study, we examined the effects of a more specific
PI-3K inhibitor (LY294002) on human CFU-E. We found that LY294002
dose-dependently inhibits the proliferation of erythroid progenitor
cells with a half-maximal effect at 10 µmol/L LY294002. LY294002 at
similar concentrations also induces apoptosis of these cells, as
evidenced by the appearance of annexin V-binding cells and DNA
fragmentation. The steady-state phosphorylation of AKT at Ser-473 that
occurs as a result of PI-3K activation was also inhibited by LY294002 at similar concentrations, suggesting that the effects of LY294002 are
specific. Interestingly, the acceleration of apoptosis by LY294002 was
observed in the presence or absence of EPO. Further, deprivation of EPO
resulted in accelerated apoptosis irrespective of the presence of
LY294002. Our study confirms and extends the finding that signaling in
human primary cultured erythroid cells is significantly different from
that in EPO-dependent cell lines. These data suggest that PI-3K has an
antiapoptotic role in erythroid progenitor cells. In addition, 2 different pathways for the protection of primary erythroid cells from
apoptosis likely exist: 1 independent of EPO that is LY294002-sensitive
and one that is EPO-dependent and at least partly insensitive to LY294002.
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