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Rexinoid-Triggered Differentiation and Tumor-Selective Apoptosis of Acute Myeloid Leukemia by Protein Kinase A–Mediated Desubordination of Retinoid X Receptor

¹ Department of Cell Biology and Signal Transduction, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch Cedex, C.U. de Strasbourg; ² Centre National de la Recherche Scientifique UMR 7151, Centre Hayem, Hôpital St. Louis, Paris, France; ³ Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli; ⁴ Centro di Oncogenomica Associazione Italiana per la Ricerca sul Cancro, CEINGE Biotecnologia Avanzata; ⁵ Ematologia con Trapianto di Cellule Staminali, Ospedale Cardarelli, Naples, Italy; ⁶ Leukaemia Research Fund Centre at the Institute of Cancer Research; and ⁷ Department of Medical and Molecular Genetics, King's College, London, United Kingdom

Requests for reprints: Hinrich Gronemeyer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, B.P. 10142, 67404 Illkirch Cedex, France. Phone: 33-3-8865-3473; Fax: 33-3-8865-3437; E-mail: hg{at}titus.u-strasbg.fr.

Apart from PML–retinoic acid receptor- (RAR) 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 RARß is blunted in mouse embryo fibroblasts lacking RARs, but reintroduction of exogenous RAR reestablishes responsiveness, thus confirming that the RAR-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.

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