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Anagrelide represses GATA-1 and FOG-1 expression without interfering with thrombopoietin receptor signal transduction

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Author
Erusalimsky, Jorge
Butcher, Lee
Singh, N.
Donovan, H.
Ahluwalia, Maninder
Date
2010
Type
Article
Publisher
Wiley
ISSN
1538-7933
Metadata
Show full item record
Abstract
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
URI
http://hdl.handle.net/10369/5285
DOI
http://dx.doi.org/10.1111/j.1538-7836.2010.03970.x
Description
The definitive version is available at www3.interscience.wiley.com
Collections
  • Cardiovascular Health and Ageing [156]

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