Anagrelide represses GATA-1 and FOG-1 expression without interfering with thrombopoietin receptor signal transduction
MetadataShow full item record
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 of Thrombosis and Haemostasis;
Journal of Thrombosis and Haemostasis, 8: 2252–2261
The definitive version is available at www3.interscience.wiley.com
Showing items related by title, author, subject and abstract.
Cross, Bethan (Cardiff Metropolitan University, 2017-06-01)Angiogenesis and inflammation are two key regulatory processes involved in chronic disease including cancer and cardiovascular disease (CVD) (Kim et al., 2013). Protein kinase B (Akt) is a serine/threonine protein kinase ...
The effects of peroxisome proliferator-activated receptor-gamma (ppar-γ) agonists on monocytic cell activation and endothelial function in diabetes Ahluwalia, Maninder (Cardiff Metropolitan University, 2005)Peroxisome Proliferator-activated Receptor-y (PPARy) is a ligand-activated transcription factor responsible for controlling genes involved in lipid and glucose metabolism. The thiazolidinediones (TZDs) are a class of ...
Evaluation of sampling methodologies for use in investigation of the health benefits of community-based exercise Thwin, Phway Phway (Cardiff Metropolitan University, 2011)Low- intensity exercise exerts therapeutic benefits on molecular pathways controlling reverse cholesterol transport, arterial stiffness and monocyte polarisation via transcription factors peroxisome proliferator-activated ...