title: Rexinoid-triggered differentiation and tumor-selective apoptosis of acute myeloid leukemia by protein kinase A-mediated desubordination of retinoid X receptor.
abstract: Apart from PML-retinoic acid receptor-alpha (RARalpha) acute promyelocytic leukemia all other acute myeloid leukemias (AML) are unresponsive to retinoid differentiation therapy. However, elevating the levels of cyclic AMP (cAMP) confers onto retinoid X receptor (RXR)-selective agonists ("rexinoids") the ability to induce terminal granulocyte differentiation and apoptosis of all-trans retinoic acid-resistant and insensitive AML cells and patients' blasts. Protein kinase A activation leads to corepressor release from the RAR subunit of the RAR-RXR heterodimer, resulting in "desubordination" of otherwise silent RXR, which acquires transcriptional competence in response to cognate ligands. Rexinoid-cAMP induction of endogenous RARbeta is blunted in mouse embryo fibroblasts lacking RARs, but reintroduction of exogenous RARalpha reestablishes responsiveness, thus confirming that the RARalpha-RXR heterodimer is the rexinoid mediator. The apoptogenic effect of this treatment involves enhanced expression of the death receptor DR5 and its cognate ligand, tumor necrosis factor-related apoptosis inducing ligand, both of which are known to induce apoptosis in a tumor cell-selective manner and lead to the activation of initiator caspases. Immunohistochemistry confirmed induction of tumor necrosis factor-related apoptosis inducing ligand and DR5 in AML patient blasts cultured ex vivo. AML patients' blasts responded to rexinoid-cAMP combination treatment with induction of maturation and apoptosis, independent of karyotype, immunophenotype, and French-American-British classification status. Clonogenic assays revealed complete inhibition of blast clonogenicity in four out of five tested samples. Our results suggest that despite the genetic, morphologic, and clinical variability of this disease, the combination of rexinoids and cAMP-elevating drugs, such as phosphodiesterase inhibitors, might lead to a novel therapeutic option for AML patients by inducing a tumor-selective death pathway.
authors.affiliation: Department of Cell Biology and Signal Transduction, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch Cedex, C.U. de Strasbourg, France.
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Aurélie
authors.initials: A
authors.lastname: Rossin
authors.forename: Oliver
authors.initials: O
authors.lastname: Hirsch
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.forename: Dominique
authors.initials: D
authors.lastname: Vitoux
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Wilhelm
authors.forename: Fabien
authors.initials: F
authors.lastname: Guidez
authors.forename: Mariacarla
authors.initials: M
authors.lastname: De Simone
authors.forename: Ettore Mariano
authors.initials: EM
authors.lastname: Schiavone
authors.forename: David
authors.initials: D
authors.lastname: Grimwade
authors.forename: Arthur
authors.initials: A
authors.lastname: Zelent
authors.forename: Hugues
authors.initials: H
authors.lastname: de Thé
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
mesh_terms: D000208:Acute Disease; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D020239:Receptor Cross-Talk; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D020298:U937 Cells
chemical_list: D010726:Phosphodiesterase Inhibitors; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; C505639:TNFRSF10B protein, human; C505640:Tnfrsf10b protein, mouse; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases