Prepublished online as a Blood First Edition Paper on October 17, 2002; DOI 10.1182/blood-2002-08-2617.
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Blood, 1 March 2003, Vol. 101, No. 5, pp. 2001-2007
RED CELLS
Induction of fetal hemoglobin expression by the histone
deacetylase inhibitor apicidin
Olaf Witt,
Sven Mönkemeyer,
Gabi Rönndahl,
Bernhard Erdlenbruch,
Dirk Reinhardt,
Katrin Kanbach, and
Arnulf Pekrun
From the Laboratory for Hematological and Cancer
Research, Children's Hospital, University of Goettingen, Goettingen,
Germany.
Pharmacologic stimulation of fetal hemoglobin (HbF) expression may
be a promising approach for the treatment of  -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,
suberoylanilide hydroxamic acid [SAHA]) and previously tested
compounds (butyrate, phenylbutyrate, isobutyramide, hydroxyurea,
5-aza-cytidine), leading to a 10-fold stimulation of HbF expression at
nanomolar to micromolar concentrations. Hyperacetylation of histones
correlated with the ability of HDAC inhibitors to stimulate HbF
synthesis. Furthermore, analysis of different mitogen-activated protein (MAP) kinase signaling pathways revealed that p38
signaling was activated following apicidin treatment of cells and that
inhibition of this pathway abolished the HbF-inducing effect of
apicidin. Additionally, activation of the A -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
pharmacologic stimulation of HbF production in erythroid cells.
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