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

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.