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Acute Leukemias

Induced differentiation of acute myeloid leukemia cells by activation of retinoid X and liver X receptors

Leukemia volumeĀ 28,Ā pages 749ā€“760 (2014)Cite this article

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Abstract

Use of all-trans retinoic acid (ATRA) as a differentiation agent has been limited to acute promyelocytic leukemia (APL) as non-APL leukemias are insensitive to ATRA. We recently demonstrated that the rexinoid, bexarotene, induces differentiation and therapeutic responses in patients with refractory AML. Rexinoids bind and activate retinoid X receptors (RXRs); however, rexinoids alone are incapable of activating retinoic acid receptor (RAR)/RXR complexes, suggesting that myeloid differentiation can occur independent of RAR. In this study, we demonstrate that rexinoid differentiation of AML cells is RAR independent and requires the expression of PU.1. Because of the promiscuousness of RXR with other nuclear receptors, myeloid differentiation by bexarotene with other nuclear receptor ligands was explored. Bexarotene cooperated with ATRA to enhance differentiation in some AML cell lines; however, the combination of bexarotene with the PPARĪ³ agonist rosiglitazone did not. In contrast, bexarotene combined with liver X receptor (LXR) agonists, T0901317 or GW3965, induced potent differentiation and cytotoxicity in AML cell lines and primary human AML cells, but not in normal progenitor cells. These results suggest that RXR/LXR-regulated gene expression in normal cells is deregulated in AML cells and identifies a potential role for these agonists in differentiation therapy of non-APLs.

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Acknowledgements

We thank the Stem Cell and Xenograft Core, the Human Immunology Core (Philadelphia, PA, USA), the Flow Cytometry Core, the Bioinformatics Core at the Perelman School of Medicine, UPENN Cancer Center and the Carroll lab for advice and assistance. This study was supported by K01-CA-129151 (PVS), 1R01CA149566 (MC), the Perelman School of Medicine at the University of Pennsylvania and the US Veterans Administration (MC).

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  1. Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    P V Sanchez,Ā S T Glantz,Ā S ScotlandĀ &Ā M Carroll

  2. Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    M T Kasner

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Correspondence to P V Sanchez.

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MC receives research support from Glaxo Smith Kline, Sanofi Aventis Corporation and Tetralogic Pharmaceuticals.

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Sanchez, P., Glantz, S., Scotland, S. et al. Induced differentiation of acute myeloid leukemia cells by activation of retinoid X and liver X receptors. Leukemia 28, 749ā€“760 (2014). https://doi.org/10.1038/leu.2013.202

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