Endogenous and combination retinoids are active in myelomonocytic leukemias
Orsola di Martino,
Haixia Niu,
Gayla Hadwiger,
Heikki Kuusanmaki,
Margaret A. Ferris,
Anh Vu,
Jeremy Beales,
Carl Wagner,
María P. Menéndez-Gutiérrez,
Mercedes Ricote,
Caroline Heckman,
John S. Welch
Affiliations
Orsola di Martino
Department of Internal Medicine, Washington University, St Louis, Missouri, 63110
Haixia Niu
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 3333
Gayla Hadwiger
Department of Internal Medicine, Washington University, St Louis, Missouri, 63110
Heikki Kuusanmaki
Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, 00014
Margaret A. Ferris
Department of Pediatrics, Washington University, St Louis, Missouri, 63110
Anh Vu
Department of Internal Medicine, Washington University, St Louis, Missouri, 63110
Jeremy Beales
Department of Internal Medicine, Washington University, St Louis, Missouri, 63110
Carl Wagner
School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona, 85281 USA
María P. Menéndez-Gutiérrez
Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029
Mercedes Ricote
Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029
Caroline Heckman
Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, 00014
John S. Welch
Department of Internal Medicine, Washington University, St Louis, Missouri, 63110
Retinoid therapy transformed response and survival outcomes in acute promyelocytic leukemia (APL), but has demonstrated only modest activity in non-APL forms of acute myeloid leukemia (AML). The presence of natural retinoids in vivo could influence the efficacy of pharmacologic agonists and antagonists. We found that natural RXRA ligands, but not RARA ligands, were present in murine MLL-AF9-derived myelomonocytic leukemias in vivo and that the concurrent presence of receptors and ligands acted as tumor suppressors. Pharmacologic retinoid responses could be optimized by concurrent targeting RXR ligands (e.g. bexarotene) and RARA ligands (e.g. all-trans retinoic acid, ATRA), which induced either leukemic maturation or apoptosis depending on cell culture conditions. Co-repressor release from the RARA:RXRA heterodimer occurred with RARA activation, but not RXRA activation, providing an explanation for the combination synergy. Combination synergy could be replicated in additional, but not all, AML cell lines and primary samples, and was associated with improved survival in vivo, although tolerability of bexarotene administration in mice remained an issue. These data provide insight into the basal presence of natural retinoids in leukemias in vivo and a potential strategy for clinical retinoid combination regimens in leukemias beyond acute promyelocytic leukemia.