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Leukemia. 2019 Jan;33(1):52-63. doi: 10.1038/s41375-018-0174-1. Epub 2018 Jun 8.

Drug targeting of NR4A nuclear receptors for treatment of acute myeloid leukemia.

Author information

1
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
2
Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX, 77030, USA.
3
New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, LA, 70560, USA.
4
Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, 77030, USA.
5
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. orlac@bcm.edu.

Abstract

NR4As are AML tumor suppressors that are frequently silenced in human acute myeloid leukemia (AML). Despite their potential as novel targets for therapeutic intervention, mechanisms of NR4A silencing and strategies for their reactivation remain poorly defined. Here we show that NR4A silencing in AML occurs through blockade of transcriptional elongation rather than epigenetic promoter silencing. By intersection of NR4A-regulated gene signatures captured upon acute, exogenous expression of NR4As in human AML cells with in silico chemical genomics screening, we identify several FDA-approved drugs including dihydroergotamine (DHE) that reactivate NR4A expression and regulate NR4A-dependent gene signatures. We show that DHE induces NR4A expression via recruitment of the super elongation complex to enable elongation of NR4A promoter paused RNA polymerase II. Finally, DHE exhibits AML selective NR4A-dependent anti-leukemic activity in cytogenetically distinct human AML cells in vitro and delays AML progression in mice revealing its potential as a novel therapeutic agent in AML.

PMID:
29884904
PMCID:
PMC6286710
DOI:
10.1038/s41375-018-0174-1
[Indexed for MEDLINE]
Free PMC Article

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