Rho kinase inhibition drives megakaryocyte polyploidization and proplatelet formation through MYC and NFE2 downregulation

Mauro P. Avanzi, Francine Goldberg, Jennifer Davila, Dante Langhi, Carlos Chiattone, William Beau Mitchell

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

The processes of megakaryocyte polyploidization and demarcation membrane system (DMS) formation are crucial for platelet production, but the mechanisms controlling these processes are not fully determined. Inhibition of Rho kinase (ROCK) signalling leads to increased polyploidization in umbilical cord blood-derived megakaryocytes. To extend these findings we determined the effect of ROCK inhibition on development of the DMS and on proplatelet formation. The underlying mechanisms were explored by analysing the effect of ROCK inhibition on the expression of MYC and NFE2, which encode two transcription factors critical for megakaryocyte development. ROCK inhibition promoted DMS formation, and increased proplatelet formation and platelet release. Rho kinase inhibition also downregulated MYC and NFE2 expression in mature megakaryocytes, and this down-regulation correlated with increased proplatelet formation. Our findings suggest a model whereby ROCK inhibition drives polyploidization, DMS growth and proplatelet formation late in megakaryocyte maturation through downregulation of MYC and NFE2 expression.

Original languageEnglish (US)
Pages (from-to)867-876
Number of pages10
JournalBritish Journal of Haematology
Volume164
Issue number6
DOIs
StatePublished - Mar 2014
Externally publishedYes

Keywords

  • MYC
  • Megakaryocytopoiesis
  • NFE2
  • Polyploidization
  • Proplatelet formation
  • Rho kinase

ASJC Scopus subject areas

  • Hematology

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