دورية أكاديمية
أعرض في EDS

Targeting Oncogenic Super Enhancers in MYC-Dependent AML Using a Small Molecule Activator of NR4A Nuclear Receptors.

التفاصيل البيبلوغرافية
العنوان: Targeting Oncogenic Super Enhancers in MYC-Dependent AML Using a Small Molecule Activator of NR4A Nuclear Receptors.
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.
References: Bonifer, C., Hoogenkamp, M., Krysinska, H. & Tagoh, H. How transcription factors program chromatin–lessons from studies of the regulation of myeloid-specific genes. Seminars in immunology 20, 257–263, https://doi.org/10.1016/j.smim.2008.05.001 (2008). (PMID: 10.1016/j.smim.2008.05.00118579409)
Sive, J. I. & Gottgens, B. Transcriptional network control of normal and leukaemic haematopoiesis. Experimental cell research 329, 255–264, https://doi.org/10.1016/j.yexcr.2014.06.021 (2014). (PMID: 10.1016/j.yexcr.2014.06.021250148934261078)
Heinz, S., Romanoski, C. E., Benner, C. & Glass, C. K. The selection and function of cell type-specific enhancers. Nature reviews. Molecular cell biology 16, 144–154, https://doi.org/10.1038/nrm3949 (2015). (PMID: 10.1038/nrm3949256508014517609)
Kuhn, M. W. et al. High-resolution genomic profiling of adult and pediatric core-binding factor acute myeloid leukemia reveals new recurrent genomic alterations. Blood 119, e67–75, https://doi.org/10.1182/blood-2011-09-380444 (2012). (PMID: 10.1182/blood-2011-09-380444222346983311263)
Shi, J. et al. Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes & development 27, 2648–2662, https://doi.org/10.1101/gad.232710.113 (2013). (PMID: 10.1101/gad.232710.113)
Ley, T. J. et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. The New England journal of medicine 368, 2059–2074, https://doi.org/10.1056/NEJMoa1301689 (2013). (PMID: 10.1056/NEJMoa130168923634996)
Groschel, S. et al. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell 157, 369–381, https://doi.org/10.1016/j.cell.2014.02.019 (2014). (PMID: 10.1016/j.cell.2014.02.01924703711)
Papaemmanuil, E. et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. The New England journal of medicine 374, 2209–2221, https://doi.org/10.1056/NEJMoa1516192 (2016). (PMID: 10.1056/NEJMoa1516192272765614979995)
Bradner, J. E., Hnisz, D. & Young, R. A. Transcriptional Addiction in Cancer. Cell 168, 629–643, https://doi.org/10.1016/j.cell.2016.12.013 (2017). (PMID: 10.1016/j.cell.2016.12.013281872855308559)
Bhagwat, A. S., Lu, B. & Vakoc, C. R. Enhancer dysfunction in leukemia. Blood 131, 1795–1804, https://doi.org/10.1182/blood-2017-11-737379 (2018). (PMID: 10.1182/blood-2017-11-737379294399515909760)
Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947, https://doi.org/10.1016/j.cell.2013.09.053 (2013). (PMID: 10.1016/j.cell.2013.09.05324119843)
Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319, https://doi.org/10.1016/j.cell.2013.03.035 (2013). (PMID: 10.1016/j.cell.2013.03.035235823223653129)
Loven, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334, https://doi.org/10.1016/j.cell.2013.03.036 (2013). (PMID: 10.1016/j.cell.2013.03.036235823233760967)
Pott, S. & Lieb, J. D. What are super-enhancers? Nature genetics 47, 8–12, https://doi.org/10.1038/ng.3167 (2015). (PMID: 10.1038/ng.316725547603)
Lam, M. T., Li, W., Rosenfeld, M. G. & Glass, C. K. Enhancer RNAs and regulated transcriptional programs. Trends in biochemical sciences 39, 170–182, https://doi.org/10.1016/j.tibs.2014.02.007 (2014). (PMID: 10.1016/j.tibs.2014.02.007246747384266492)
Pefanis, E. et al. RNA exosome-regulated long non-coding RNA transcription controls super-enhancer activity. Cell 161, 774–789, https://doi.org/10.1016/j.cell.2015.04.034 (2015). (PMID: 10.1016/j.cell.2015.04.034259576854428671)
Liang, J. et al. Epstein-Barr virus super-enhancer eRNAs are essential for MYC oncogene expression and lymphoblast proliferation. Proceedings of the National Academy of Sciences of the United States of America 113, 14121–14126, https://doi.org/10.1073/pnas.1616697113 (2016). (PMID: 10.1073/pnas.1616697113278645125150416)
Hnisz, D. et al. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Molecular cell 58, 362–370, https://doi.org/10.1016/j.molcel.2015.02.014 (2015). (PMID: 10.1016/j.molcel.2015.02.014258011694402134)
Bahr, C. et al. A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies. Nature 553, 515–520, https://doi.org/10.1038/nature25193 (2018). (PMID: 10.1038/nature2519329342133)
Roe, J. S., Mercan, F., Rivera, K., Pappin, D. J. & Vakoc, C. R. BET Bromodomain Inhibition Suppresses the Function of Hematopoietic Transcription Factors in Acute Myeloid Leukemia. Molecular cell 58, 1028–1039, https://doi.org/10.1016/j.molcel.2015.04.011 (2015). (PMID: 10.1016/j.molcel.2015.04.011259821144475489)
Luo, H. et al. c-Myc rapidly induces acute myeloid leukemia in mice without evidence of lymphoma-associated antiapoptotic mutations. Blood 106, 2452–2461, https://doi.org/10.1182/blood-2005-02-0734 (2005). (PMID: 10.1182/blood-2005-02-073415972450)
Brondfield, S. et al. Direct and indirect targeting of MYC to treat acute myeloid leukemia. Cancer Chemother Pharmacol 76, 35–46, https://doi.org/10.1007/s00280-015-2766-z (2015). (PMID: 10.1007/s00280-015-2766-z259567094485702)
Kim, J. et al. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 143, 313–324, https://doi.org/10.1016/j.cell.2010.09.010 (2010). (PMID: 10.1016/j.cell.2010.09.010209469883018841)
Nie, Z. et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151, 68–79, https://doi.org/10.1016/j.cell.2012.08.033 (2012). (PMID: 10.1016/j.cell.2012.08.033230212163471363)
Nanbakhsh, A. et al. c-Myc regulates expression of NKG2D ligands ULBP1/2/3 in AML and modulates their susceptibility to NK-mediated lysis. Blood 123, 3585–3595, https://doi.org/10.1182/blood-2013-11-536219 (2014). (PMID: 10.1182/blood-2013-11-536219246775444198341)
Fauriat, C. & Olive, D. AML drug resistance: c-Myc comes into play. Blood 123, 3528–3530, https://doi.org/10.1182/blood-2014-04-566711 (2014). (PMID: 10.1182/blood-2014-04-56671124904096)
Li, L. et al. SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells. Cell stem cell 15, 431–446, https://doi.org/10.1016/j.stem.2014.08.001 (2014). (PMID: 10.1016/j.stem.2014.08.001252802194305398)
Pelish, H. E. et al. Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature 526, 273–276, https://doi.org/10.1038/nature14904 (2015). (PMID: 10.1038/nature14904264167494641525)
Zuber, J. et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478, 524–528, https://doi.org/10.1038/nature10334 (2011). (PMID: 10.1038/nature103342181420021814200)
Bhagwat, A. S. et al. BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements. Cell reports 15, 519–530, https://doi.org/10.1016/j.celrep.2016.03.054 (2016). (PMID: 10.1016/j.celrep.2016.03.054270684644838499)
Zhao, Y. et al. High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML. Cell reports 16, 2003–2016, https://doi.org/10.1016/j.celrep.2016.07.032 (2016). (PMID: 10.1016/j.celrep.2016.07.032274988704996374)
Mullican, S. E. et al. Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nature medicine 13, 730–735, https://doi.org/10.1038/nm1579 (2007). (PMID: 10.1038/nm157917515897)
Boudreaux, S. P. et al. Drug targeting of NR4A nuclear receptors for treatment of acute myeloid leukemia. Leukemia 33, 52–63, https://doi.org/10.1038/s41375-018-0174-1 (2019). (PMID: 10.1038/s41375-018-0174-129884904)
Boudreaux, S. P., Ramirez-Herrick, A. M., Duren, R. P. & Conneely, O. M. Genome-wide profiling reveals transcriptional repression of MYC as a core component of NR4A tumor suppression in acute myeloid leukemia. Oncogenesis 1, e19, https://doi.org/10.1038/oncsis.2012.19 (2012). (PMID: 10.1038/oncsis.2012.19235527353412651)
Thakore, P. I. et al. Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements. Nature methods 12, 1143–1149, https://doi.org/10.1038/nmeth.3630 (2015). (PMID: 10.1038/nmeth.3630265015174666778)
Kim, T. K. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187, https://doi.org/10.1038/nature09033 (2010). (PMID: 10.1038/nature0903330200793020079)
Danko, C. G. et al. Identification of active transcriptional regulatory elements from GRO-seq data. Nature methods 12, 433–438, https://doi.org/10.1038/nmeth.3329 (2015). (PMID: 10.1038/nmeth.3329257994414507281)
Sims, R. J. III, Belotserkovskaya, R. & Reinberg, D. Elongation by RNA polymerase II: the short and long of it. Genes & development 18, 2437–2468, https://doi.org/10.1101/gad.1235904 (2004). (PMID: 10.1101/gad.1235904)
Hargreaves, D. C., Horng, T. & Medzhitov, R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138, 129–145, https://doi.org/10.1016/j.cell.2009.05.047 (2009). (PMID: 10.1016/j.cell.2009.05.047195962402828818)
Peterlin, B. M. & Price, D. H. Controlling the elongation phase of transcription with P-TEFb. Molecular cell 23, 297–305, https://doi.org/10.1016/j.molcel.2006.06.014 (2006). (PMID: 10.1016/j.molcel.2006.06.01416885020)
Ni, Z. et al. P-TEFb is critical for the maturation of RNA polymerase II into productive elongation in vivo. Molecular and cellular biology 28, 1161–1170, https://doi.org/10.1128/MCB.01859-07 (2008). (PMID: 10.1128/MCB.01859-0718070927)
Melo, C. A. et al. eRNAs are required for p53-dependent enhancer activity and gene transcription. Molecular cell 49, 524–535, https://doi.org/10.1016/j.molcel.2012.11.021 (2013). (PMID: 10.1016/j.molcel.2012.11.02123273978)
Pnueli, L., Rudnizky, S., Yosefzon, Y. & Melamed, P. RNA transcribed from a distal enhancer is required for activating the chromatin at the promoter of the gonadotropin alpha-subunit gene. Proceedings of the National Academy of Sciences of the United States of America 112, 4369–4374, https://doi.org/10.1073/pnas.1414841112 (2015). (PMID: 10.1073/pnas.1414841112258102544394321)
Greer, C. B. et al. Histone Deacetylases Positively Regulate Transcription through the Elongation Machinery. Cell reports 13, 1444–1455, https://doi.org/10.1016/j.celrep.2015.10.013 (2015). (PMID: 10.1016/j.celrep.2015.10.013265494584934896)
Hsieh, C. L. et al. Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. Proceedings of the National Academy of Sciences of the United States of America 111, 7319–7324, https://doi.org/10.1073/pnas.1324151111 (2014). (PMID: 10.1073/pnas.1324151111247782164034202)
Panigrahi, A. K. et al. SRC-3 Coactivator Governs Dynamic Estrogen-Induced Chromatin Looping Interactions during Transcription. Molecular cell 70, 679–694.e677, https://doi.org/10.1016/j.molcel.2018.04.014 (2018). (PMID: 10.1016/j.molcel.2018.04.014297755825966282)
Jin, F. et al. A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 503, 290–294, https://doi.org/10.1038/nature12644 (2013). (PMID: 10.1038/nature12644241419503838900)
Mertz, J. A. et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proceedings of the National Academy of Sciences of the United States of America 108, 16669–16674, https://doi.org/10.1073/pnas.1108190108 (2011). (PMID: 10.1073/pnas.1108190108219493973189078)
Dawson, M. A. et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529–533, https://doi.org/10.1038/nature10509 (2011). (PMID: 10.1038/nature10509219643403679520)
Wagner, E. J. & Carpenter, P. B. Understanding the language of Lys36 methylation at histone H3. Nature reviews. Molecular cell biology 13, 115–126, https://doi.org/10.1038/nrm3274 (2012). (PMID: 10.1038/nrm3274222667613969746)
Winter, G. E. et al. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376–1381, https://doi.org/10.1126/science.aab1433 (2015). (PMID: 10.1126/science.aab1433259993704937790)
Dawson, M. A. et al. Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia. Leukemia 28, 311–320, https://doi.org/10.1038/leu.2013.338 (2014). (PMID: 10.1038/leu.2013.33824220271)
Rathert, P. et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature 525, 543–547, https://doi.org/10.1038/nature14898 (2015). (PMID: 10.1038/nature14898263677984921058)
Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073, https://doi.org/10.1038/nature09504 (2010). (PMID: 10.1038/nature095042087159620871596)
Doroshow, D. B., Eder, J. P. & LoRusso, P. M. BET inhibitors: a novel epigenetic approach. Annals of oncology: official journal of the European Society for Medical Oncology 28, 1776–1787, https://doi.org/10.1093/annonc/mdx157 (2017). (PMID: 10.1093/annonc/mdx157)
Bolden, J. E. et al. Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition. Cell reports 8, 1919–1929, https://doi.org/10.1016/j.celrep.2014.08.025 (2014). (PMID: 10.1016/j.celrep.2014.08.025252423224234106)
Fong, C. Y. et al. BET inhibitor resistance emerges from leukaemia stem cells. Nature 525, 538–542, https://doi.org/10.1038/nature14888 (2015). (PMID: 10.1038/nature148882636779626367796)
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
الوصف
تدمد:2045-2322
DOI:10.1038/s41598-020-59469-3