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

A. Azouz, Y. L. Wu, J. Hillion, I. Tarkanyi, A. Karniguian, J. Aradi, M. Lanotte, G. Q. Chen, M. Chehna, E. Segal-Bendirdjian

Research output: Contribution to journalArticle

20 Citations (Scopus)

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-LR1 SFD), 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-LR1 SFD 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-LR1 SFD 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.

Original languageEnglish
Pages (from-to)613-622
Number of pages10
JournalLeukemia
Volume24
Issue number3
DOIs
Publication statusPublished - Mar 2010

Keywords

  • APL
  • Differentiation
  • Resistance
  • Retinoid
  • Telomerase
  • WT1

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells'. Together they form a unique fingerprint.

  • Cite this

    Azouz, A., Wu, Y. L., Hillion, J., Tarkanyi, I., Karniguian, A., Aradi, J., Lanotte, M., Chen, G. Q., Chehna, M., & Segal-Bendirdjian, E. (2010). Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells. Leukemia, 24(3), 613-622. https://doi.org/10.1038/leu.2009.283