Autonomous rexinoid death signaling is suppressed by converging signaling pathways in immature leukemia cells

On their own, retinoid X receptor (RXR)-selective ligands (rexinoids) are s ilent in retinoic acid receptor (RAR)-RXR heterodimers, and no selective re xinoid program has been described as yet in cellular systems. We report her e on the rexinoid signaling capacity that triggers apoptosis of immature pr omyelocytic NB4 cells as a default pathway in the absence of survival facto rs. Rexinoid-induced apoptosis displays all features of bona fide programme d cell death and is inhibited by RXR, but not RAR antagonists. Several type s of survival signals block rexinoid-induced apoptosis. RAR alpha agonists switch the cellular response toward differentiation and induce the expressi on of antiapoptosis factors. Activation of the protein kinase A pathway in the presence of rexinoid agonists induces maturation and blocks immature ce ll apoptosis. Addition of nonretinoid serum factors also blocks cell death but does not induce cell differentiation. Rexinoid-induced apoptosis is lin ked to neither the presence nor stability of the promyelocytic leukemia-RAR alpha fusion protein and operates also in non-acute promyelocytic leukemia cells. Together our results support a model according to which rexinoids a ctivate in certain leukemia cells a default death pathway onto which severa l other signaling paradigms converge. This pathway is entirely distinct fro m that triggered by RAR agonists, which control cell maturation and postmat uration apoptosis.