J of Thrombosis Haemost - 2015 - Ahluwalia - The gene expression signature of anagrelide provides an insight into its.pdf (390.32 kB)
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The gene expression signature of anagrelide provides an insight into its mechanism of action and uncovers new regulators of megakaryopoiesis

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posted on 25.03.2022, 16:05 by Maninder Ahluwalia, Lee ButcherLee Butcher, Hannah Donovan, Clare Killick-Cole, Paul M. Jones, Jorge D. Erusalimsky
BACKGROUND: 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.

History

Published in

Journal of Thrombosis and Haemostasis

Publisher

Wiley

Version

VoR (Version of Record)

Citation

Ahluwalia 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. 1103–1112

Print ISSN

1538-7933

Electronic ISSN

1538-7836

Cardiff Met Affiliation

  • Cardiff School of Sport and Health Sciences

Cardiff Met Authors

Maninder Ahluwalia Lee Butcher Jorge Erusalimsky

Cardiff Met Research Centre/Group

  • Cardiovascular Metabolism and Inflammation
  • Cellular Senescence and Pathophysiology

Copyright Holder

© The Authors

Language

en