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Retinoic acid targets DNA-methyltransferases and histone deacetylases during APL blast differentiation in vitro and in vivo

Oncogene volume 24, pages 1820–1830 (2005)Cite this article

Abstract

The acute promyelocytic leukemia (PML)-retinoic acid receptor α (RARα) fusion product recruits histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activities on retinoic acid (RA)-target promoters causing their silencing and differentiation block. RA treatment induces epigenetic modifications at its target loci and restores myeloid differentiation of APL blasts. Using RA-sensitive and RA-resistant APL cell lines and primary blasts, we addressed the functional relevance of the aberrant methylation status at the RA-target promoter RARβ2 and the mechanism by which methylation is reversed by RA. RA decreased DNMT expression and activity, which correlated with demethylation at specific sites on RARβ2 promoter/exon-1, and the ability of APL blasts to differentiate in vitro and in vivo. None of these events occurred in an RA-resistant APL cell line containing a PML-RARα defective for ligand binding. The specific contribution of the HDAC and DNMT pathways to the response of APL cells to RA was also tested by inhibiting these enzymatic activities with TSA and/or 5-azacytidine. In RA-responsive and RA-resistant APL blasts, TSA and 5-azacytidine induced specific changes on the chromatin state at RA-target sites, increased the RA effect on promoter activity, endogenous RA-target gene expression and differentiation. These results extend the rationale for chromatin-targeted treatment in APL and RA-resistant leukemias.

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Acknowledgements

This work was supported by Associazione Italiana per la Ricerca sul Cancro, European Community (QLG1-CT-2001-01935), Italian Ministry of Health, National Program on Stem Cells, Ministry of University and Research (Cofin and FIRB) and Fondazione Cenci Bolognetti. LT is supported by a fellowship from FIRC. WHM is a scientist of the Canadian Institutes of Health Research.

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Authors and Affiliations

  1. San Raffaele Bio-medical Science Park of Rome, Rome, Italy

    Francesco Fazi, Lorena Travaglini & Clara Nervi

  2. Departments of Histology and Medical Embryology, University ‘La Sapienza’, Rome, Italy

    Francesco Fazi, Lorena Travaglini & Clara Nervi

  3. Biochemical Sciences, University ‘La Sapienza’, Rome, Italy

    Daniela Carotti & Franco Palitti

  4. Cellular Biotechnology and Hematology, University ‘La Sapienza’, Rome, Italy

    Daniela Diverio

  5. European Institute of Oncology (IEO), Milan, Italy

    Myriam Alcalay & Pier Giuseppe Pelicci

  6. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy

    Myriam Alcalay & Pier Giuseppe Pelicci

  7. Lady Davis Institute for Medical Research, Sir Mortimer B Davis Jewish General Hospital and McGill University Department of Oncology and Medicine, Montreal, Quebec, Canada

    Suzan McNamara & Wilson H Miller Jr

  8. Department of Biopathology, University Tor Vergata, Rome

    Francesco Lo Coco

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  1. Francesco Fazi
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Correspondence to Clara Nervi.

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Fazi, F., Travaglini, L., Carotti, D. et al. Retinoic acid targets DNA-methyltransferases and histone deacetylases during APL blast differentiation in vitro and in vivo. Oncogene 24, 1820–1830 (2005). https://doi.org/10.1038/sj.onc.1208286

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