1. ¹INSERM U685, Centre Hayem, Hôpital St Louis, 1 avenue Claude Vellefaux, 75475 Paris, France
2. ²INSERM U362, Institut Gustave Roussy, 39 rue Camille-Desmoulins, 94805 Villejuif, France

Correspondence: F Besançon, E-mail: francoise.besancon@stlouis.inserm.fr

Received 19 January 2005; Revised 16 May 2005; Accepted 27 May 2005; Published online 25 July 2005.

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-B 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-B activation did not affect granulocytic differentiation. Importantly, NF-B 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-B 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-B 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-B signalling may contribute to an accumulation of mature APL cells and participate in the development of ATRA syndrome.