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Role of the histone deacetylase complex in acute promyelocytic leukaemia
1Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
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.
Insights
Mutant retinoic acid receptors (RARs) drive leukemia by altering chromatin. Histone deacetylase inhibitors restore retinoid treatment effectiveness in resistant acute promyelocytic leukemia (APL) patients.
Area of Science:
- Molecular Biology
- Oncology
- Epigenetics
Background:
- Non-liganded retinoic acid receptors (RARs) repress gene transcription via histone deacetylase (HDAC) complex recruitment.
- Mutant RARalpha, formed by PML-RARalpha or PLZF-RARalpha translocations, causes acute promyelocytic leukemia (APL).
- PML-RARalpha APL responds to retinoic acid (RA), while PLZF-RARalpha APL shows poor response.
Purpose of the Study:
- To investigate how chimeric RARs associate with the HDAC complex.
- To determine the role of this association in APL development and retinoid response.
- To explore the therapeutic potential of HDAC inhibitors in APL.
Main Methods:
- Analysis of chimeric receptor association with the HDAC complex.
- Assessment of retinoid sensitivity in APL cell lines.
- Treatment of APL cell lines with histone deacetylase inhibitors and retinoids.
Main Results:
- The association of PML-RARalpha and PLZF-RARalpha with the HDAC complex influences APL development and retinoid responsiveness.
- Histone deacetylase inhibitors significantly enhance retinoid-induced differentiation in RA-sensitive APL cell lines.
- Histone deacetylase inhibitors restore retinoid responsiveness in RA-resistant APL cell lines.
Conclusions:
- Oncogenic RARs contribute to leukaemogenesis through aberrant chromatin acetylation.
- Targeting nuclear receptor co-factors with HDAC inhibitors offers a potential therapeutic strategy for APL.
- This approach may improve treatment outcomes for patients with retinoid-resistant APL.