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Ferrata Storti Foundation
Haematologica 2021 Volume 106(4):1008-1021
Acute Myeloid Leukemia
Endogenous and combination retinoids are active in myelomonocytic leukemias
Orsola di Martino,1 Haixia Niu,2 Gayla Hadwiger,1 Heikki Kuusanmaki,3 Margaret A. Ferris,4 Anh Vu,1 Jeremy Beales,1 Carl Wagner,5
María P. Menéndez-Gutiérrez,6 Mercedes Ricote,6 Caroline Heckman3 and John S. Welch1
1Department of Internal Medicine, Washington University, St Louis, MO, USA; 2Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; 3Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; 4Department of Pediatrics, Washington University, St Louis, MO, USA; 5School of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, USA and 6Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
ABSTRACT
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 pharma- cologic agonists and antagonists. We found that natural RXRA ligands, but not RARA ligands, were present in murine MLL-AF9-derived myelomono- cytic leukemias in vivo and that the concurrent presence of receptors and lig- ands acted as tumor suppressors. Pharmacologic retinoid responses could be optimized by concurrent targeting of RXR ligands (e.g., bexarotene) and RARA ligands (e.g., all-trans retinoic acid), 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 syn- ergy. Combination synergy could be replicated in additional, but not all, AML cell lines and primary samples, and was associated with improved sur- vival in vivo, although tolerability of bexarotene administration in mice remained an issue. These data provide insight into the basal presence of nat- ural retinoids in leukemias in vivo and a potential strategy for clinical retinoid combination regimens in leukemias beyond APL.
Introduction
The retinoic acid receptors (RAR) and retinoid X receptors (RXR) are ligand-acti- vated transcription factors that influence hematopoietic stem cell self-renewal and differentiation.1-3 Transcriptional activation of the retinoid receptors is ligand dependent.4 Therefore, the potential activity of retinoid receptors in leukemogene- sis may be altered depending on the availability of natural ligands within a leukemic population, and retinoid receptors might act as either tumor suppressors or onco- genes depending on the ligand context. However, in leukemia, it is not known whether these receptors are exposed to natural activating ligands in vivo, or whether different forms of leukemia might contain different quantities of functional ligands.
There are three different RAR and RXR isoforms (α, β, and γ) that are differently expressed in hematopoietic cells.5,6 RARA and RXRA expression are dynamically regulated during myeloid maturation, with highest mRNA expression in mature neutrophils.7 RAR function as obligate heterodimers with RXR, whereas RXR can form either homodimers or heterodimers with other orphan nuclear receptors (e.g., peroxisome proliferator-activated receptors [PPAR], liver X receptors [LXR], etc.).4 RAR-RXR dimers bind DNA with high affinity at specific retinoic acid response ele- ments (RARE) in target gene promoters/enhancers.8 RAR-RXR acts as a transcrip- tional repressor by binding co-repressor complexes composed by nuclear receptor
Correspondence:
JOHN S. WELCH
jwelch@wustl.edu
Received: June 26, 2020. Accepted: November 16, 2020. Pre-published: February 4, 2021.
https://doi.org/10.3324/haematol.2020.264432
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