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Autonomous Rexinoid Death Signaling Is Suppressed by Converging Signaling Pathways in Immature Leukemia Cells

INSERM U-496 (G.R.B., M.F., J.H, Z.B., L.L., E.S.-B., M.L.) Centre G. Hayem Hôpital Saint-Louis 75010 Paris, France
INSERM U-365 (F.B.) Institut Curie 75248 Paris Cedex 05, France
Institut de Génétique et de Biologie Moléculaire et Cellulaire (L.A., A.R., F.H.G.) Centre Nationale de la Recherche Scientifique/INSERM/ULP BP 163, 67404 Illkirch Cedex C. U. de Strasbourg, France
Istituto di Patologia generale e Oncologia (L.A.) Seconda Università degli studi di Napoli Piazzetta S. Andrea delle Dame 2 80138, Napoli, Italy

On their own, retinoid X receptor (RXR)-selective ligands (rexinoids) are silent in retinoic acid receptor (RAR)-RXR heterodimers, and no selective rexinoid program has been described as yet in cellular systems. We report here on the rexinoid signaling capacity that triggers apoptosis of immature promyelocytic NB4 cells as a default pathway in the absence of survival factors. Rexinoid-induced apoptosis displays all features of bona fide programmed cell death and is inhibited by RXR, but not RAR antagonists. Several types of survival signals block rexinoid-induced apoptosis. RAR agonists switch the cellular response toward differentiation and induce the expression of antiapoptosis factors. Activation of the protein kinase A pathway in the presence of rexinoid agonists induces maturation and blocks immature cell apoptosis. Addition of nonretinoid serum factors also blocks cell death but does not induce cell differentiation. Rexinoid-induced apoptosis is linked to neither the presence nor stability of the promyelocytic leukemia-RAR fusion protein and operates also in non-acute promyelocytic leukemia cells. Together our results support a model according to which rexinoids activate in certain leukemia cells a default death pathway onto which several other signaling paradigms converge. This pathway is entirely distinct from that triggered by RAR agonists, which control cell maturation and postmaturation apoptosis.

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