Show simple item record

dc.contributor.authorErusalimsky, Jorge
dc.contributor.authorButcher, Lee
dc.contributor.authorSingh, N.
dc.contributor.authorDonovan, H.
dc.contributor.authorAhluwalia, Maninder
dc.date.accessioned2014-02-10T16:49:41Z
dc.date.available2014-02-10T16:49:41Z
dc.date.issued2010
dc.identifier.citationJournal of Thrombosis and Haemostasis, 8: 2252–2261en_US
dc.identifier.issn1538-7933
dc.identifier.urihttp://hdl.handle.net/10369/5285
dc.descriptionThe definitive version is available at www3.interscience.wiley.comen_US
dc.description.abstractBackground: 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.en_US
dc.language.isoenen_US
dc.publisherWileyen_US
dc.relation.ispartofseriesJournal of Thrombosis and Haemostasis;
dc.subjectanagrelideen_US
dc.subjectmegakaryocyteen_US
dc.subjectsignal transductionen_US
dc.subjectthrombocythemiaen_US
dc.subjectthrombopoietinen_US
dc.subjecttranscription factoren_US
dc.titleAnagrelide represses GATA-1 and FOG-1 expression without interfering with thrombopoietin receptor signal transductionen_US
dc.typeArticleen_US
dc.identifier.doihttp://dx.doi.org/10.1111/j.1538-7836.2010.03970.x


Files in this item

FilesSizeFormatView

There are no files associated with this item.

This item appears in the following collection(s)

Show simple item record