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

Bishton, MJ; Harrison, SJ; Martin, BP; McLaughlin, N; James, C; Josefsson, EC; Henley, KJ; Kile, BT; Prince, HM; Johnstone, RW

Author(s): Bishton, MJ; Harrison, SJ; Martin, BP; McLaughlin, N; James, C; Josefsson, EC; Henley, KJ; Kile, BT; Prince, HM; Johnstone, RW;
Details: Publication Year 2011-03-31,Volume 117,Issue #13,Page 3658-3668
Journal Title: BLOOD
Publication Type: Journal Article
Abstract: 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)
Publisher: AMER SOC HEMATOLOGY
Keywords: HUMAN MEGAKARYOCYTE GROWTH; KINASE RHO-KINASE; LIGHT-CHAIN; PROPLATELET FORMATION; P21-ACTIVATED KINASE; CONTROLLED-TRIAL; PLATELET COUNTS; DOUBLE-BLIND; MYOSIN; CANCER
Publisher's Version: https://doi.org/10.1182/blood-2010-11-318055
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2011-03-31 12:00:00