cFos Mediates cAMP-Dependent Generation of ROS and Rescue of Maturation Program in Retinoid-Resistant Acute Promyelocytic Leukemia Cell Line NB4-LR1 |
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| Authors: | Jean-Luc Carrier Pasha Javadi Emilie Bourrier Céline Camus Evelyne Ségal-Bendirdjian A?da Karniguian |
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| Affiliation: | 1. INSERM UMR-S 1007, Paris, France.; 2. Université Paris Descartes, Sorbonne Paris Cité, Paris, France.; Institut Jacques Monod, France, |
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| Abstract: | A determining role has been assigned to cAMP in the signaling pathways that relieve resistance to anti-leukemia differentiation therapy. However, the underlying mechanisms have not been elucidated yet. Here, we identify cFos as a critical cAMP effector, able to regulate the re-expression and splicing of epigenetically silenced genes associated with maturation (CD44) in retinoid-resistant NB4-LR1 leukemia cells. Furthermore, using RNA interference approach, we show that cFos mediates cAMP-induced ROS generation, a critical mediator of neutrophil maturation, and in fine differentiation. This study highlights some of the mechanisms by which cAMP acts to overcome resistance, and reveals a new alternative cFos-dependent pathway which, though nonexistent in retinoid-sensitive NB4 cells, is essential to rescue the maturation program of resistant cells. |
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