Rexinoid-triggered differentiation and tumor-selective apoptosis of acute myeloid leukemia by protein kinase A-mediated desubordination of retinoid X receptor

Lucia Altucci, Aurélie Rossin, Oliver Hirsch, Angela Nebbioso, Dominique Vitoux, Emmanuelle Wilhelm, Fabien Guidez, Mariacarla De Simone, Ettore Mariano Schiavone, David Grimwade, Arthur Zelent, Hugues De Thé, Hinrich Gronemeyer

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)8754-8765
Number of pages12
JournalCancer Research
Volume65
Issue number19
DOIs
StatePublished - Oct 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Altucci, L., Rossin, A., Hirsch, O., Nebbioso, A., Vitoux, D., Wilhelm, E., Guidez, F., De Simone, M., Schiavone, E. M., Grimwade, D., Zelent, A., De Thé, H., & Gronemeyer, H. (2005). Rexinoid-triggered differentiation and tumor-selective apoptosis of acute myeloid leukemia by protein kinase A-mediated desubordination of retinoid X receptor. Cancer Research, 65(19), 8754-8765. https://doi.org/10.1158/0008-5472.CAN-04-3569