Histone deacetylase inhibitors induce caspase‐dependent apoptosis and downregulation of daxx in acute promyelocytic leukaemia with t(15;17)

Abstract

Histone deacetylase (HDAC) appears to play an important role in the pathogenesis of acute promyelocytic leukaemia (APL) as it is recruited by both PML–RARα and PLZF/RARα in leukaemic cells with t(15;17) and t(11;17) respectively. Recent studies have demonstrated that HDAC inhibitors can be therapeutically used in various neoplastic disorders including APL. Cell differentiation was considered the major mechanism of the anti‐leukaemic effects of HDAC inhibitors in APL. However, most of these studies either evaluated the effect of HDAC inhibitors in combination with all‐trans retinoic acid (ATRA) or focused on the less common form of APL with t(11;17). To investigate the cellular effects of HDAC inhibitors, including sodium butyrate, trichostatin A, and suberoylanilide hydroxamic acid (SAHA), we used two APL cell lines, NB4 and the ATRA‐resistant derivative NB4.306. Moreover, primary cells from five patients with cytogenetic evidence for t(15;17) were also studied. Our results demonstrated that HDAC inhibitors induce distinct caspase‐dependent apoptosis in APL, which showed both concentration‐and time‐dependence. In addition, changes in the apoptosis‐regulatory proteins, daxx, bcl‐2 and bax were analysed. HDAC inhibitors induced downregulation of daxx, but no significant changes were detected in bcl‐2 or bax. In conclusion, apoptosis induced by HDAC inhibitors in APL could provide an effective strategy for treatment of patients with t(15;17).