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Retinoic acid downmodulates erythroid differentiation and GATA1 expression
in purified adult-progenitor culture
C Labbaye, M Valtieri, U Testa, A Giampaolo, E Meccia, P Sterpetti, I Parolini, E Pelosi, D Bulgarini and YE Cayre
Thomas Jefferson Cancer Institute, Thomas Jefferson University,
Philadelphia, PA 19107-5541.
All-trans retinoic acid (RA) is an important morphogen in vertebrate
development, a normal constituent in human adult blood and is also involved
in the control of cell growth and differentiation in acute promyelocytic
leukemia. We have examined the effects of RA on normal hematopoiesis by
using early hematopoietic progenitor cells (HPC) stringently purified from
adult peripheral blood. In clonogenetic fetal calf serum-supplemented
(FCS+) or -nonsupplemented (FCS-) culture treated with saturating levels of
interleukin-3 (IL-3) granulocyte- macrophage colony-stimulating factor
(GM-CSF) and erythropoietin (Ep) (combined with c-kit ligand in
FCS(-)-culture conditions), RA induces a dramatic dose-dependent shift from
erythroid to granulomonocytic colony formation, the latter colonies being
essentially represented by granulocytic clones. This shift is apparently
not caused by a recruitment phenomenon, because in FCS+ culture, the total
number of colonies is not significantly modified by RA addition. In FCS-
liquid- suspension culture supplemented with saturating Ep level and
low-dose IL-3/GM-CSF, adult HPC undergo unilineage erythropoietic
differentiation: Here again, treatment with high-dose RA induces a shift
from the erythroid to granulocytic differentiation pathway. Studies on RA
time-response or pulse treatment in semisolid or liquid culture show that
early RA addition is most effective, thus indicating that early but not
late HPC are sensitive to its action. We then analyzed the expression of
the master GATA1 gene, which encodes a finger transcription factor required
for normal erythroid development; addition of RA to HPC stimulated into
unilineage erythropoietic differentiation in liquid culture caused a
virtually complete inhibition of GATA1 mRNA induction. These results
indicate that RA directly inhibits the erythroid differentiation program at
the level of early adult HPC, and may lead to a shift from the erythroid to
granulocytic differentiation pathway. This phenomenon is correlated with
inhibition of GATA1 induction in the early stages of erythropoietic
differentiation.
Volume 83,
Issue 3,
pp. 651-656,
02/01/1994
Copyright © 1994 by The American Society of Hematology
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