title: cFos mediates cAMP-dependent generation of ROS and rescue of maturation program in retinoid-resistant acute promyelocytic leukemia cell line NB4-LR1.
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.
authors.affiliation: INSERM UMR-S 1007, Paris, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Carrier
authors.forename: Pasha
authors.initials: P
authors.lastname: Javadi
authors.forename: Emilie
authors.initials: E
authors.lastname: Bourrier
authors.forename: Céline
authors.initials: C
authors.lastname: Camus
authors.forename: Evelyne
authors.initials: E
authors.lastname: Ségal-Bendirdjian
authors.forename: Aïda
authors.initials: A
authors.lastname: Karniguian
mesh_terms: D017398:Alternative Splicing; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D005091:Exons; D014644:Genetic Variation; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D009504:Neutrophils / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D012176:Retinoids / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D017931:DNA Primers; D018960:Hyaluronan Receptors; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012176:Retinoids; D000242:Cyclic AMP