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Drug Targeting of NR4A Nuclear Receptors for Treatment of Acute Myeloid Leukemia
NR4As are AML tumor suppressors that are frequently silenced in human 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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286710/ https://www.ncbi.nlm.nih.gov/pubmed/29884904 http://dx.doi.org/10.1038/s41375-018-0174-1 |
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author | Boudreaux, Seth P. Duren, Ryan P. Call, Steven G. Nguyen, Loc Freire, Pablo R Narayanan, Padmini Redell, Michele S. Conneely, Orla M. |
author_facet | Boudreaux, Seth P. Duren, Ryan P. Call, Steven G. Nguyen, Loc Freire, Pablo R Narayanan, Padmini Redell, Michele S. Conneely, Orla M. |
author_sort | Boudreaux, Seth P. |
collection | PubMed |
description | NR4As are AML tumor suppressors that are frequently silenced in human 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. |
format | Online Article Text |
id | pubmed-6286710 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
record_format | MEDLINE/PubMed |
spelling | pubmed-62867102018-12-09 Drug Targeting of NR4A Nuclear Receptors for Treatment of Acute Myeloid Leukemia Boudreaux, Seth P. Duren, Ryan P. Call, Steven G. Nguyen, Loc Freire, Pablo R Narayanan, Padmini Redell, Michele S. Conneely, Orla M. Leukemia Article NR4As are AML tumor suppressors that are frequently silenced in human 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. 2018-06-08 2019-01 /pmc/articles/PMC6286710/ /pubmed/29884904 http://dx.doi.org/10.1038/s41375-018-0174-1 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Boudreaux, Seth P. Duren, Ryan P. Call, Steven G. Nguyen, Loc Freire, Pablo R Narayanan, Padmini Redell, Michele S. Conneely, Orla M. Drug Targeting of NR4A Nuclear Receptors for Treatment of Acute Myeloid Leukemia |
title | Drug Targeting of NR4A Nuclear Receptors for Treatment of Acute Myeloid Leukemia |
title_full | Drug Targeting of NR4A Nuclear Receptors for Treatment of Acute Myeloid Leukemia |
title_fullStr | Drug Targeting of NR4A Nuclear Receptors for Treatment of Acute Myeloid Leukemia |
title_full_unstemmed | Drug Targeting of NR4A Nuclear Receptors for Treatment of Acute Myeloid Leukemia |
title_short | Drug Targeting of NR4A Nuclear Receptors for Treatment of Acute Myeloid Leukemia |
title_sort | drug targeting of nr4a nuclear receptors for treatment of acute myeloid leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286710/ https://www.ncbi.nlm.nih.gov/pubmed/29884904 http://dx.doi.org/10.1038/s41375-018-0174-1 |
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