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Retinoid-induced activation of NF-κB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells

Oncogene volume 24, pages 7145–7155 (2005)Cite this article

Abstract

All-trans retinoic acid (ATRA) significantly improves the survival of patients with acute promyelocytic leukemia (APL) by inducing granulocytic differentiation of leukemia cells. Since an activation of the transcription factor NF-κB occurs during ATRA-induced maturation of APL cells, a mechanistic link between these two processes was investigated. Using an in vitro model for APL, we report that ectopic overexpression of a repressor of NF-κB activation did not affect granulocytic differentiation. Importantly, NF-κB inhibition markedly resulted in a decreased viability of the differentiated cells, which correlated with increased apoptosis. Apoptosis was accompanied by a sustained activation of the c-Jun N-terminal kinase (JNK). Inhibition of JNK by the specific inhibitor SP600125 or by transfection of a dominant-negative mutant of JNK1 reduced the percentage of apoptotic cells, thus showing that JNK activation constitutes a death signal. Furthermore, impairment of NF-κB activation resulted in increased levels of reactive oxygen species (ROS) upon ATRA treatment. ROS accumulation was suppressed by the antioxidant butylated hydroxyanisol, which also abolished ATRA-induced JNK activation and apoptosis. Altogether, our results demonstrate an antiapoptotic effect of NF-κB activation during ATRA-induced differentiation of NB4 cells and identify repression of ROS-mediated JNK activation as a mechanism for this effect. Our observations also suggest that NF-κB signalling may contribute to an accumulation of mature APL cells and participate in the development of ATRA syndrome.

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Acknowledgements

This work was supported by INSERM and by grants from the Ligue Nationale contre le Cancer and the Association pour la Recherche sur le Cancer.

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Authors and Affiliations

  1. INSERM U685, Centre Hayem, Hôpital St Louis, 1 avenue Claude Vellefaux, Paris, 75475, France

    Julie Mathieu, Michel Lanotte & Françoise Besançon

  2. INSERM U362, Institut Gustave Roussy, 39 rue Camille-Desmoulins, Villejuif, 94805, France

    Stéphane Giraudier

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  1. Julie Mathieu
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  2. Stéphane Giraudier
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Correspondence to Françoise Besançon.

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Mathieu, J., Giraudier, S., Lanotte, M. et al. Retinoid-induced activation of NF-κB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells. Oncogene 24, 7145–7155 (2005). https://doi.org/10.1038/sj.onc.1208889

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