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Prepublished online as a Blood First Edition Paper on October 17, 2002; DOI 10.1182/blood-2002-08-2617.

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Submitted September 3, 2002
Accepted October 1, 2002

Induction of fetal hemoglobin expression by the histone-deacetylase inhibitor apicidin

Olaf Witt*, Sven Moenkemeyer, Gabi Roenndahl, Bernhard Erdlenbruch, Dirk Reinhardt, Katrin Kanbach, and Arnulf Pekrun

Children's Hospital, University of Goettingen, Goettingen, Germany
Children's Hospital, Division of Hematology/Oncology, University of Muenster, Muenster, Germany

* Corresponding author; email: owitt{at}gwdg.de.

Pharmacologic stimulation of fetal hemoglobin (HbF) expression may be a promising approach for the treatment of ß-thalassemia. In this study, we have investigated the HbF-inducing activity and molecular mechanisms of specific histone-deacetylase (HDAC)-inhibitors in human K562 erythroleukemia cells. Apicidin was the most potent agent compared with other HDAC-inhibitors (Trichostatin A, MS-275, HC-Toxin, SAHA) and previously tested compounds (butyrate, phenylbutyrate, isobutyramide, hydroxyurea, 5-aza-cytidine), leading to a 10fold stimulation of HbF-expression at nano- to micromolar concentrations. Hyperacetylation of histones correlated with the ability of HDAC-inhibitors to stimulate HbF-synthesis. Furthermore, analysis of different MAP kinase signaling pathways revealed that p38 signaling was activated following apicidin-treatment of cells and inhibition of this pathway abolished the HbF-inducing effect of apicidin. Additionally, activation of the A{gamma}-globin promoter by apicidin could be inhibited by p38-inhibitor SB203580. In summary, the novel HDAC-inhibitor apicidin was found to be a potent inducer of HbF-synthesis in K562 cells. The present data outline the role of histone-hyperacetylation and p38 MAP kinase signaling as molecular targets for pharmacological stimulation of HbF-production in erythroid cells.


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