دورية أكاديمية
Targeting Oncogenic Super Enhancers in MYC-Dependent AML Using a Small Molecule Activator of NR4A Nuclear Receptors.
العنوان: | Targeting Oncogenic Super Enhancers in MYC-Dependent AML Using a Small Molecule Activator of NR4A Nuclear Receptors. |
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المؤلفون: | Call SG; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.; Molecular and Cellular Biology PhD Program, Baylor College of Medicine, Houston, TX, 77030, USA., Duren RP; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.; Integrative Molecular and Biomedical Sciences PhD Program, Baylor College of Medicine, Houston, TX, 77030, USA., Panigrahi AK; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA., Nguyen L; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA., Freire PR; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.; Molecular and Cellular Biology PhD Program, Baylor College of Medicine, Houston, TX, 77030, USA., Grimm SL; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, 77030, USA., Coarfa C; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, 77030, USA., Conneely OM; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. orlac@bcm.edu.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. orlac@bcm.edu. |
المصدر: | Scientific reports [Sci Rep] 2020 Feb 18; Vol. 10 (1), pp. 2851. Date of Electronic Publication: 2020 Feb 18. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: London : Nature Publishing Group, copyright 2011- |
مواضيع طبية MeSH: | Enhancer Elements, Genetic/*genetics , Leukemia, Myeloid, Acute/*drug therapy , Nuclear Receptor Subfamily 4, Group A, Member 1/*genetics , Proto-Oncogene Proteins c-myc/*genetics, Animals ; Cell Cycle Proteins/genetics ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Reprogramming/genetics ; Dihydroergotamine/pharmacology ; E1A-Associated p300 Protein/genetics ; Epigenesis, Genetic/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/pathology ; Mice ; Nuclear Receptor Subfamily 4, Group A, Member 1/agonists ; Oncogenes/genetics ; Signal Transduction/drug effects ; Transcription Factors/genetics ; Xenograft Model Antitumor Assays |
مستخلص: | Epigenetic reprogramming in Acute Myeloid Leukemia (AML) leads to the aberrant activation of super enhancer (SE) landscapes that drive the expression of key oncogenes, including the oncogenic MYC pathway. These SEs have been identified as promising therapeutic targets, and have given rise to a new class of drugs, including BET protein inhibitors, which center on targeting SE activity. NR4A nuclear receptors are tumor suppressors of AML that function in part through transcriptional repression of the MYC-driven oncogenic program via mechanisms that remain unclear. Here we show that NR4A1, and the NR4A inducing drug dihydroergotamine (DHE), regulate overlapping gene expression programs in AML and repress transcription of a subset of SE-associated leukemic oncogenes, including MYC. NR4As interact with an AML-selective SE cluster that governs MYC transcription and decommissions its activation status by dismissing essential SE-bound coactivators including BRD4, Mediator and p300, leading to loss of p300-dependent H3K27 acetylation and Pol 2-dependent eRNA transcription. DHE shows similar efficacy to the BET inhibitor JQ1 at repressing SE-dependent MYC expression and AML growth in mouse xenografts. Thus, DHE induction of NR4As provides an alternative strategy to BET inhibitors to target MYC dependencies via suppression of the AML-selective SE governing MYC expression. |
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معلومات مُعتمدة: | R01 CA160747 United States CA NCI NIH HHS; P30 ES030285 United States ES NIEHS NIH HHS; P30 CA125123 United States CA NCI NIH HHS |
المشرفين على المادة: | 0 (BRD4 protein, human) 0 (Cell Cycle Proteins) 0 (MYC protein, human) 0 (NR4A1 protein, human) 0 (Nuclear Receptor Subfamily 4, Group A, Member 1) 0 (Proto-Oncogene Proteins c-myc) 0 (Transcription Factors) 436O5HM03C (Dihydroergotamine) EC 2.3.1.48 (E1A-Associated p300 Protein) EC 2.3.1.48 (EP300 protein, human) |
تواريخ الأحداث: | Date Created: 20200220 Date Completed: 20201113 Latest Revision: 20210217 |
رمز التحديث: | 20240628 |
مُعرف محوري في PubMed: | PMC7029036 |
DOI: | 10.1038/s41598-020-59469-3 |
PMID: | 32071334 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2045-2322 |
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DOI: | 10.1038/s41598-020-59469-3 |