RAR-independent RXR signaling induces t(15;17) leukemia cell maturation.
Although retinoic acid receptor alpha (RARalpha) agonists induce the maturation of t(15;17) acute promyelocytic leukemia (APL) cells, drug treatment also selects leukemic blasts expressing PML-RARalpha fusion proteins with mutated ligand-binding domains that no longer respond to all-trans retinoic acid (ATRA). Here we report a novel RARalpha-independent signaling pathway that induces maturation of both ATRA-sensitive and ATRA-resistant APL NB4 cells, and does not invoke the ligand-induced alteration of PML-RARalpha signaling, stability or compartmentalization. This response involves a cross-talk between RXR agonists and protein kinase A signaling. Our results indicate the existence of a separate RXR-dependent maturation pathway that can be activated in the absence of known ligands for RXR heterodimerization partners.
Benoit
G
G
INSERM U496, Centre G.Hayem, Hôpital Saint-Louis, 1, Avenue Claude Vellefaux, 75010 Paris.
Altucci
L
L
Flexor
M
M
Ruchaud
S
S
Lillehaug
J
J
Raffelsberger
W
W
Gronemeyer
H
H
Lanotte
M
M
D000595:Amino Acid Sequence; D001483:Base Sequence; D001565:Benzoates / Q000494:pharmacology; D001752:Blast Crisis; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000502:physiology; D020239:Receptor Cross-Talk; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*; D014178:Translocation, Genetic; D014212:Tretinoin / Q000494:pharmacology
D001565:Benzoates; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C082925:retinoic acid receptor beta; C087130:SR 11237; D014212:Tretinoin; D017868:Cyclic AMP-Dependent Protein Kinases