Anagrelide represses GATA-1 and FOG-1 expression without interfering with thrombopoietin receptor signal transduction
Author
Erusalimsky, Jorge
Butcher, Lee
Singh, N.
Donovan, H.
Ahluwalia, Maninder
Date
2010Type
Article
Publisher
Wiley
ISSN
1538-7933
Metadata
Show full item recordAbstract
Background: Anagrelide is a selective inhibitor of
megakaryocytopoiesis used to treat thrombocytosis in patients
with chronic myeloproliferative disorders. The effectiveness of
anagrelide in lowering platelet counts is firmly established, but
its primary mechanism of action remains elusive. Objectives and
Methods: Here, we have evaluated whether anagrelide interferes
with the major signal transduction cascades stimulated by
thrombopoietin in the hematopoietic cell line UT-7/mpl and in
cultured CD34+-derived human hematopoietic cells. In addition,
we have used quantitative mRNA expression analysis to
assess whether the drug affects the levels of known transcription
factors that control megakaryocytopoiesis. Results: In UT-7/
mpl cells, anagrelide (1 lM) did not interfere with MPLmediated
signaling as monitored by its lack of effect on JAK2
phosphorylation. Similarly, the drug did not affect the phosphorylation
of STAT3, ERK1/2 or AKT in either UT-7/mpl
cells or primary hematopoietic cells. In contrast, during
thrombopoietin-induced megakaryocytic differentiation of normal
hematopoietic cultures, anagrelide (0.3 lM) reduced the rise
in the mRNA levels of the transcription factors GATA-1 and
FOG-1 as well as those of the downstream genes encoding FLI-
1, NF-E2, glycoprotein IIb and MPL. However, the drug
showed no effect on GATA-2 or RUNX-1 mRNA expression.
Furthermore, anagrelide did not diminish the rise in GATA-1
and FOG-1 expression during erythropoietin-stimulated erythroid
differentiation. Cilostamide, an exclusive and equipotent
phosphodiesterase III (PDEIII) inhibitor, did not alter the
expression of these genes. Conclusions: Anagrelide suppresses
megakaryocytopoiesis by reducing the expression levels of
GATA-1 and FOG-1 via a PDEIII-independent mechanism
that is differentiation context-specific and does not involve
inhibition of MPL-mediated early signal transduction events.
Journal/conference proceeding
Journal of Thrombosis and Haemostasis;
Citation
Journal of Thrombosis and Haemostasis, 8: 2252–2261
Description
The definitive version is available at www3.interscience.wiley.com
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