Blood Journal
Leading the way in experimental and clinical research in hematology

Deciphering the molecular and biological processes that mediate histone deacetylase inhibitor-induced thrombocytopenia

  1. Mark J Bishton1,
  2. Simon J Harrison2,
  3. Benjamin P Martin1,
  4. Nicole McLaughlin1,
  5. Chloé James3,
  6. Emma C Josefsson3,
  7. Katya J Henley3,
  8. Benjamin T Kile4,
  9. H. Miles Prince2, and
  10. Ricky W Johnstone1,*
  1. 1 Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;
  2. 2 Haematology Service, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;
  3. 3 Molecular Medicine Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia;
  4. 4 University of Melbourne, Parkville, VIC, Australia
  1. * Corresponding author; email: ricky.johnstone{at}petermac.org
This article has an Erratum 125(24):3824
This article has an Erratum 125(24):3824

Abstract

Histone deacetylase inhibitor (HDACi)-induced thrombocytopenia (TCP) is a major dose limiting toxicity of this new class of drugs. Using pre-clinical models to study the molecular and biological events that underpin this effect of HDACi we found C57BL/6 mice treated with both the HDAC1/2-selective HDACi romidepsin and the pan-HDACi panobinostat developed significant TCP. HDACi-induced TCP was not due to myelosuppression or reduced platelet lifespan, but decreased platelet release from megakaryocytes. Cultured primary murine megakaryocytes showed reductions in pro-platelet extensions following HDACi exposure and a dose-dependent increase in the phosphorylation of myosin light chain 2 (MLC). The phosphorylation status of the MLC (pMLC) and subsequent pro-platelet formation in megakaryocytes is regulated by Rho GTPase proteins Rac1, CDC42 and RhoA. Primary mouse megakaryocytes and the human megakaryoblastic cell line Meg-01 showed reductions in Rac1, CDC42 and RhoA protein levels following treatment with HDACi. Importantly, we were able to overcome HDACi-induced TCP by administering the mouse-specific TPO-mimetic AMP-4, which improved platelet numbers to levels similar to untreated controls. Our report provides the first detailed account of the molecular and biological processes involved in HDACi-mediated TCP. Moreover our pre-clinical studies provide evidence that dose-limiting TCP induced by HDACi may be circumvented using a TPO mimetic.

  • Submitted November 12, 2010.
  • Accepted January 10, 2011.