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Transcriptional Control and Signal Transduction

Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells

Leukemia volume 24, pages 613–622 (2010)Cite this article

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Abstract

The expression of hTERT gene, encoding the catalytic subunit of telomerase, is a feature of most cancer cells. Changes in the chromatin environment of its promoter and binding of transcriptional factors have been reported in differentiating cells when its transcription is repressed. However, it is not clear whether these changes are directly involved in this repression or only linked to differentiation. In a maturation-resistant acute promyelocytic leukemia (APL) cell line (NB4-LR1), we have previously identified a new pathway of retinoid-induced hTERT repression independent of differentiation. Using a variant of this cell line (NB4-LR1SFD), which resists to this repression, we show that although distinct patterns of histone modifications and transcription factor binding at the proximal domain of hTERT gene promoter could concur to modulate its expression, this region is not sufficient to the on/off switch of hTERT by retinoids. DNA methylation analysis of the hTERT promoter led to the identification of two distinct functional domains, a proximal one, fully unmethylated in both cell lines, and a distal one, significantly methylated in NB4-LR1SFD cells, whose methylation was further re-enforced by retinoid treatment. Interestingly, we showed that the binding to this distal domain of a known hTERT repressor, WT1, was defective only in NB4-LR1SFD cells. We propose that epigenetic modifications targeting this distal region could modulate the binding of hTERT repressors and account either for hTERT reactivation and resistance to retinoid-induced hTERT downregulation.

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Acknowledgements

This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale, the Association pour la Recherche contre le Cancer (E S-B), the Fondation de France (E S-B), Cent pour Sang la Vie and Capucine (E S-B), the Société Française du Cancer, the Société Française d'Hématologie (IT) and Aleppo Pharmaceutical Industries (Alpha), Aleppo, Syria (AA). We thank Dr Sophie Bombard (UMR CNRS 8601) for her comments on the paper and Dr Michèle Goodhardt (INSERM U662) for her critical discussions and English editing of the paper.

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Authors and Affiliations

  1. INSERM UMR-S 1007, Paris, France

    A Azouz, J Hillion, A Karniguian, M Lanotte & E Ségal-Bendirdjian

  2. Université Paris Descartes, Paris, France

    A Azouz, J Hillion, A Karniguian, M Lanotte & E Ségal-Bendirdjian

  3. Research Center of Pharmaceutical Chemistry, University of Aleppo, Aleppo, Syria

    A Azouz & M Chehna

  4. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao-Tong University School of Medicine, Shanghai, China

    Y-L Wu & G-Q Chen

  5. Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    I Tarkanyi & J Aradi

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  1. A Azouz
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Correspondence to E Ségal-Bendirdjian.

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Azouz, A., Wu, YL., Hillion, J. et al. Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells. Leukemia 24, 613–622 (2010). https://doi.org/10.1038/leu.2009.283

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