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

Historic deacetylase (HDAC) appears to play an important role in the pathogenesis of acute promyelocytic leukaemia (APL) as it is recruited by both PML-RAR alpha and PLZF/RAR alpha 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).