Journal
BLOOD
Volume 117, Issue 13, Pages 3658-3668Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-11-318055
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Funding
- National Health and Medical Research Council of Australia
- Australian Rotary Health
- Sylvia and Charles Viertel Foundation
- Leukemia & Lymphoma Society
- Melbourne University
- [516725]
- [575535]
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Histone deacetylase inhibitor (HDACI)-induced thrombocytopenia (TCP) is a major dose-limiting toxicity of this new class of drugs. Using preclinical models to study the molecular and biologic events that underpin this effect of HDACI, we found that 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 life-span, but to decreased platelet release from megakaryocytes. Cultured primary murine megakaryocytes showed reductions in pro-platelet extensions after HDACI exposure and a dose-dependent increase in the phosphorylation of myosin light chain 2 (MLC2). Phosphorylation of MLC to phospho-MLC (pMLC) and subsequent proplatelet formation in megakaryocytes is regulated by the 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 after treatment with HDACIs. We were able to overcome HDACI-induced TCP by administering the mouse-specific thrombopoietin (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 biologic processes involved in HDACI-mediated TCP. Moreover, our preclinical studies provide evidence that dose-limiting TCP induced by HDACIs may be circumvented using a TPO mimetic. (Blood. 2011;117(13):3658-3668)
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