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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-05-1477.
Submitted May 23, 2002
Accepted October 8, 2002
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*
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
Department of Hematology and Oncology, Istituto Superiore di Sanita', Rome, Italy
* Corresponding author; email: cesare.peschle{at}mail.tju.edu.
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). Since 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 (BFU-Es). The GC derivative dexamethasone (Dex) was tested in minibulk cultures at graded dosages within the therapeutical range (10-6-10-9M). Dex did not exert significant effects alone, but synergistically potentiated the action of KL in a dose-dependent fashion. Specifically, Dex induced (i) a delayed erythroid maturation coupled with a two-log increased number of generated erythroblasts, (ii) an enhanced HbF synthesis up to 85% F cells and 55%  -globin content at terminal maturation (i.e., in > 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 modulation of -globin expression rather than recruitment of BFU-Es with elevated HbF synthetic potential. At 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. Since Dex acts at dosages utilized in immunological disease therapy, KL+Dex administration may be considered to develop pre-clinical models for  -hemoglobinopathy treatment.
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