Abstract
Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex through a class of silencing mediators termed SMRT or N-CoR. Mutant forms of RARalpha, created by chromosomal translocations with either the PML (for promyelocytic leukaemia) or the PLZF (for promyelocytic leukaemia zinc finger) locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML-RARalpha APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF-RARalpha patients respond very poorly, if at all. 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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / therapeutic use
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Cell Line
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Cloning, Molecular
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Drug Resistance, Neoplasm
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Enzyme Inhibitors / pharmacology
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Escherichia coli
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Hematopoiesis
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Histone Deacetylase Inhibitors
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Histone Deacetylases / metabolism*
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Hydroxamic Acids / pharmacology
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Leukemia, Promyelocytic, Acute / drug therapy
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Leukemia, Promyelocytic, Acute / enzymology*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Nuclear Proteins*
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Nuclear Receptor Co-Repressor 2
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / metabolism
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Repressor Proteins / metabolism
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Retinoic Acid Receptor alpha
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae Proteins*
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Sin3 Histone Deacetylase and Corepressor Complex
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tretinoin / metabolism
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Tretinoin / therapeutic use
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Tumor Suppressor Proteins
Substances
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Antineoplastic Agents
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DNA-Binding Proteins
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Enzyme Inhibitors
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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NCOR2 protein, human
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Neoplasm Proteins
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Nuclear Proteins
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Nuclear Receptor Co-Repressor 2
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Oncogene Proteins, Fusion
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RARA protein, human
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Receptors, Retinoic Acid
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Repressor Proteins
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Retinoic Acid Receptor alpha
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SIN3 protein, S cerevisiae
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SIN3A transcription factor
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Saccharomyces cerevisiae Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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trichostatin A
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Tretinoin
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Histone Deacetylases
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Sin3 Histone Deacetylase and Corepressor Complex