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A novel mechanism of retinoic acid resistance in acute promyelocytic leukemia cells through a defective pathway in telomerase regulation

Leukemia volume 16, pages 826–832 (2002)Cite this article

Abstract

Human telomerase, a cellular reverse transcriptase specifically activated in most malignant tumors and usually inactive in normal somatic cells, plays an important role in immortalization and tumorigenesis. Early reports have indicated that terminal differentiation of various cells is associated with a rapid inhibition of telomerase activity, preceded by a down-regulation of telomerase reverse transcriptase (hTERT) mRNA. Recently, we have shown that telomerase can be repressed by all-trans retinoic acid (ATRA) independently of terminal maturation during long-term ATRA treatment of the maturation-resistant promyelocytic leukemia cell line (NB4-R1), leading to shortening of telomeres and cell death, events overcome by ectopic hTERT expression. Here, we report the isolation of a variant of NB4-R1 cells (NB4-R1SFD), which bypasses this death step, because of a re-activated telomerase, despite the continuous presence of ATRA. While unresponsive to a long-term maturation independent regulation of telomerase by ATRA, these cells retain a functional pathway of telomerase down-regulation associated with retinoid-induced maturation. These findings reinforce the notion that two distinct pathways of telomerase regulation by retinoids co-exist in APL cells. Noteworthy, we show that the slow developing mechanism, that causes death of maturation-resistant cells, is subjected to a new type of retinoid-resistance as yet not understood.

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Acknowledgements

This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Ligue Nationale contre le Cancer and the Association pour la Recherche contre le Cancer (ARC Nos 5384, and 5707). TS and FP were supported by the Coopération Franco-Algérienne, and the Ministère de la Recherche et de la Technologie, respectively. We thank Dr G Chabot (INSERM U496) for critical reading of the manuscript.

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  1. INSERM U496, Centre G Hayem, Hôpital Saint-Louis, Paris, France

    F Pendino, T Sahraoui, M Lanotte & E Ségal-Bendirdjian

  2. Département de Biologie, Université Es-Sénia, Faculté des Sciences, Oran, Algeria

    T Sahraoui

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Pendino, F., Sahraoui, T., Lanotte, M. et al. A novel mechanism of retinoic acid resistance in acute promyelocytic leukemia cells through a defective pathway in telomerase regulation. Leukemia 16, 826–832 (2002). https://doi.org/10.1038/sj.leu.2402470

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