Role of the histone deacetylase complex in acute promyelocytic leukaemia

Richard J. Lin, Laszlo Nagy, Satoshi Inoue, Wenlin Shao, Wilson H. Miller and Ronald M. Evans ()
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Richard J. Lin: Howard Hughes Medical Institute
Laszlo Nagy: Howard Hughes Medical Institute
Satoshi Inoue: The Salk Institute for Biological Studies
Wenlin Shao: Lady Davis Institute for Medical Research
Wilson H. Miller: Lady Davis Institute for Medical Research
Ronald M. Evans: Howard Hughes Medical Institute

Nature, 1998, vol. 391, issue 6669, 811-814

Abstract: Abstract Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex1,2,3 through a class of silencing mediators termed SMRT or N-CoR4,5. Mutant forms of RARα, created by chromosomal translocations with either the PML (for promyelocytic leukaemia)6,7,8 or the PLZF (for promyelocytic leukaemia zinc finger)9,10 locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML–RARα APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF–RARα patients respond very poorly, if at all11. Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation of nuclear receptor co-factors may be a useful approach in the treatment of human disease.

Date: 1998
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DOI: 10.1038/35895

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