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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing
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Cell Line, Tumor
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Cell Membrane / metabolism
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Cyclic AMP / metabolism*
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DNA Primers / genetics
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Drug Resistance, Neoplasm
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Epigenesis, Genetic
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Exons
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Genetic Variation
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Humans
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Hyaluronan Receptors / biosynthesis
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Neutrophils / metabolism
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Proto-Oncogene Proteins c-fos / metabolism*
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RNA Interference
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RNA, Messenger / metabolism
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Reactive Oxygen Species
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Retinoids / pharmacology*
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Time Factors
Substances
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DNA Primers
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Hyaluronan Receptors
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Proto-Oncogene Proteins c-fos
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RNA, Messenger
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Reactive Oxygen Species
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Retinoids
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Cyclic AMP
Grants and funding
This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM,
www.inserm.fr/) and the Ligue Nationale Contre le Cancer (Comité de Paris,
http://www.ligue-cancer.net/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.