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Acute myeloid leukemia

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

Leukemia volume 33, pages 52–63 (2019)Cite this article

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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.

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Acknowledgements

This work was supported by RO1 CA160747 from National Institutes of Health to OMC and by the Cell Sorting and Flow Cytometry shared resource of the Dan L. Duncan Comprehensive Cancer Center with funding from National Cancer Institute grant (P30CA125123). The authors acknowledge the joint participation by Adrienne Helis Melvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with Baylor College of Medicine. The authors also thank Dr. Terzah Horton and the Leukemia Research Interest Group at Texas Children’s Hospital for providing primary patient AML samples.

Statement of significance

A chemical genomics strategy identifies DHE as a novel activator of silenced NR4A tumor suppressors with repositioning potential for treatment of AML.

Author contributions

S.P.B., R.P.D., and S.G.C. carried out experiments including CMap chemical genomics integration, ChIP-experiments, bisulfite sequencing, and cell growth assays. P.R.F. did flow cytometry analysis. L.N. did transplantation assays. P.N., M.S.R., and P.R.F. were responsible for colony forming assays on primary AML samples. S.P.B. and O.M.C. conceived the strategy, designed experiments and wrote the paper.

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Author notes

  1. Seth P. Boudreaux

    Present address: New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, LA, 70560, USA

  2. These authors contributed equally: Seth P. Boudreaux, Ryan P. Duren.

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    Seth P. Boudreaux, Ryan P. Duren, Steven G. Call, Loc Nguyen, Pablo R. Freire & Orla M. Conneely

  2. Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX, 77030, USA

    Seth P. Boudreaux & Ryan P. Duren

  3. Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, 77030, USA

    Padmini Narayanan & Michele S. Redell

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  1. Seth P. Boudreaux
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Correspondence to Orla M. Conneely.

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Boudreaux, S.P., Duren, R.P., Call, S.G. et al. Drug targeting of NR4A nuclear receptors for treatment of acute myeloid leukemia. Leukemia 33, 52–63 (2019). https://doi.org/10.1038/s41375-018-0174-1

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