EMBO Journal 1999-12-15

RAR-independent RXR signaling induces t(15;17) leukemia cell maturation.

G Benoit, L Altucci, M Flexor, S Ruchaud, J Lillehaug, W Raffelsberger, H Gronemeyer, M Lanotte

Index: EMBO J. 18(24) , 7011-8, (1999)

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Abstract

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.