Article
- The EMBO Journal (1999) 18, 7011 - 7018
- doi:10.1093/emboj/18.24.7011
RAR-independent RXR signaling induces t(15;17) leukemia cell maturation
Gérard Benoit1, Lucia Altucci2, Maria Flexor1, Sandrine Ruchaud1, Johan Lillehaug1,3, Wolfgang Raffelsberger2, Hinrich Gronemeyer2 and Michel Lanotte1
- INSERM U496, Centre G.Hayem, Hôpital Saint-Louis, 1, Avenue Claude Vellefaux, 75010 Paris, France
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)/CNRS/INSERM/ULP, BP 163, 67404 Illkirch Cedex, C.U. de Strasbourg, France
- Present address: Department of Molecular Biology, Bergen High Technology Centre (BHTC), University of Bergen, N-5020, Norway
Correspondence to:
Michel Lanotte, E-mail: mlanotte@jupiter.chu-stlouis.fr
Hinrich Gronemeyer, E-mail: hg@igbmc.u-strasbg.fr
Received 12 August 1999; Accepted 22 October 1999; Revised 22 October 1999
Abstract
Although retinoic acid receptor alpha (RAR
) agonists induce the maturation of t(15;17) acute promyelocytic leukemia (APL) cells, drug treatment also selects leukemic blasts expressing PML–RAR fusion proteins with mutated ligand-binding domains that no longer respond to all-trans retinoic acid (ATRA). Here we report a novel RAR-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–RAR 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.
Keywords:
- differentiation,
- leukemia,
- nuclear receptors,
- protein kinase A,
- retinoids,
- signal transduction
