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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-05-1477.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2826-2832
RED CELLS
HbF reactivation in sibling BFU-E colonies: synergistic
interaction of kit ligand with low-dose dexamethasone
Marco Gabbianelli,
Ugo Testa,
Adriana Massa,
Ornella Morsilli,
Ernestina Saulle,
Nadia Maria Sposi,
Eleonora Petrucci,
Gualtiero Mariani, and
Cesare Peschle
From the Department of Hematology and Oncology,
Istituto Superiore di Sanità, Rome, Italy; and the
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.
Mechanisms underlying fetal hemoglobin (HbF) reactivation in stress
erythropoiesis have not been fully elucidated. We suggested that a key
role is played by kit ligand (KL). Because glucocorticoids (GCs)
mediate stress erythropoiesis, we explored their capacity to potentiate
the stimulatory effect of KL on HbF reactivation, as evaluated in
unilineage erythropoietic culture of purified adult progenitors
(erythroid burst-forming units [BFU-Es]). The GC derivative
dexamethasone (Dex) was tested in minibulk cultures at graded dosages
within the therapeutical range (10 6 to 109
M). Dex did not exert significant effects alone, but synergistically it
potentiated the action of KL in a dose-dependent fashion. Specifically, Dex induced delayed erythroid maturation coupled with a 2-log increased
number of generated erythroblasts and enhanced HbF synthesis up to 85%
F cells and 55%  -globin content at terminal maturation (ie, in more
than 80%-90% mature erythroblasts). Equivalent results were obtained
in unicellular erythroid cultures of sibling BFU-Es treated with KL
alone or combined with graded amounts of Dex. These results indicate
that the stimulatory effect of KL + Dex is related to the
modulation of -globin expression rather than to recruitment of
BFU-Es with elevated HbF synthetic potential. At the molecular level,
Id2 expression is totally suppressed in control erythroid culture but
is sustained in KL + Dex culture. Hypothetically, Id2 may mediate
the expansion of early erythroid cells, which correlates with HbF
reactivation. These studies indicate that GCs play an important role in
HbF reactivation. Because Dex acts at dosages used in immunologic
disease therapy, KL + Dex administration may be considered to
develop preclinical models for  -hemoglobinopathy treatment.
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