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dc.contributor.authorAhluwalia, Maninder
dc.contributor.authorButcher, Lee
dc.contributor.authorDonovan, Hannah
dc.contributor.authorKillick-Cole, Clare
dc.contributor.authorJones, Paul M.
dc.contributor.authorErusalimsky, Jorge
dc.date.accessioned2016-03-21T11:18:50Z
dc.date.available2016-03-21T11:18:50Z
dc.date.issued2015-05-09
dc.identifier.citationAhluwalia M, Butcher L, Donovan H, Killick-Cole C, Jones PM, Erusalimsky JD (2015) 'The gene expression signature of anagrelide provides an insight into its mechanism of action and uncovers new regulators of megakaryopoiesis', Journal of Thrombosis and Haemostasis, 13 (6), pp. 1103–1112en_US
dc.identifier.issn1538-7933
dc.identifier.urihttp://hdl.handle.net/10369/7789
dc.descriptionThis article was published in Journal of Thrombosis and Haemostasis on 9 May 2015 (online), available open access at http://dx.doi.org/10.1111/jth.12959 The author's post-print was made available in this repository from 09 May 2016en_US
dc.description.abstractBACKGROUND: Anagrelide is a cytoreductive agent used to lower platelet counts in essential thrombocythemia. Although the drug has been known to selectively inhibit megakaryopoiesis for many years, the molecular mechanism accounting for this activity is still unclear. OBJECTIVES AND METHODS: To address this issue we have compared the global gene expression profiles of human hematopoietic cells treated ex-vivo with and without anagrelide while growing under megakaryocyte differentiation conditions, using high-density oligonucleotide microarrays. Gene expression data were validated by the quantitative polymerase chain reaction and mined to identify functional subsets and regulatory pathways. RESULTS: We identified 328 annotated genes differentially regulated by anagrelide, including many genes associated with platelet functions and with the control of gene transcription. Prominent among the latter was TRIB3, whose expression increased in the presence of anagrelide. Pathway analysis revealed that anagrelide up-regulated genes that are under the control of the transcription factor ATF4, a known TRIB3 inducer. Notably, immunoblot analysis demonstrated that anagrelide induced the phosphorylation of eIF2α, which is an upstream regulator of ATF4, and increased ATF4 protein levels. Furthermore, salubrinal, an inhibitor of eIF2α dephosphorylation, increased the expression of ATF4-regulated genes and blocked megakaryocyte growth.en_US
dc.language.isoenen_US
dc.publisherWiley Online Libraryen_US
dc.relation.ispartofseriesJournal of Thrombosis and Haemostasis
dc.rightsCreative Commons Attribution Non-Commercial No Derivatives License
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectactivating transcription factor 4en_US
dc.subjectanagrelideen_US
dc.subjecteukaryotic initiation factor-2en_US
dc.subjectalpha subuniten_US
dc.subjectmegakaryocyteen_US
dc.subjectthrombocytosisen_US
dc.titleThe gene expression signature of anagrelide provides an insight into its mechanism of action and uncovers new regulators of megakaryopoiesisen_US
dc.typeArticleen_US
dc.identifier.doihttp://dx.doi.org/10.1111/jth.12959
dc.date.dateAccepted2015-04-07
dcterms.dateAccepted2015-04-02


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