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

Br J Haematol. 2001 Nov;115(2):287-97. doi: 10.1046/j.1365-2141.2001.03123.x.


Histone deacetylase (HDAC) appears to play an important role in the pathogenesis of acute promyelocytic leukaemia (APL) as it is recruited by both PML-RARalpha 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).

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Aged
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Butyrates / pharmacology
  • Carrier Proteins / metabolism
  • Caspases / physiology
  • Chromosomes, Human, Pair 15
  • Chromosomes, Human, Pair 17
  • Co-Repressor Proteins
  • Down-Regulation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Intracellular Signaling Peptides and Proteins*
  • Leukemia, Promyelocytic, Acute / genetics
  • Leukemia, Promyelocytic, Acute / metabolism
  • Leukemia, Promyelocytic, Acute / pathology*
  • Middle Aged
  • Molecular Chaperones
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins*
  • Translocation, Genetic
  • Tumor Cells, Cultured
  • Vorinostat


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Butyrates
  • Carrier Proteins
  • Co-Repressor Proteins
  • DAXX protein, human
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • Neoplasm Proteins
  • Nuclear Proteins
  • trichostatin A
  • Vorinostat
  • Caspases