Compounds targeting class II histone deacetylases do not cause panHDACI-associated impairment of megakaryocyte differentiation.

Abstract:

:Histone deacetylase inhibitors (HDACIs) have demonstrated effectiveness against lymphomas and myelomas in clinical practice. However, common to all currently approved broad-acting HDACIs (panHDACIs) is dose-limiting thrombocytopenia, which has prevented wider use in cancer therapy. Using CD34+ hematopoietic stem cells (HSCs), we show that megakaryocyte (MK) cell maturation and differentiation are impaired by panHDACIs, correlating to clinical thrombocytopenia. Importantly, we demonstrate that inhibitors of class II histone deacetylases (HDACs), including LMK235 and tubacin at clinically relevant concentrations, do not affect MK maturation. Furthermore, we show that HDACI-induced impairment of MK differentiation is associated with reduction of protein levels of the transcription factor GATA-1, but not tubulin hyperacetylation. Finally, we report that panHDACIs trigger a rapid loss of GATA-1 protein via a proteasome-dependent pathway. Our data support the notion that specifically targeting class II HDACs in cancer treatment is a potential strategy that would offer a safer alternative than current panHDACIs.

journal_name

Exp Hematol

journal_title

Experimental hematology

authors

Simic D,Sang N

doi

10.1016/j.exphem.2018.12.007

subject

Has Abstract

pub_date

2019-04-01 00:00:00

pages

36-46

eissn

0301-472X

issn

1873-2399

pii

S0301-472X(19)30005-0

journal_volume

72

pub_type

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