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  Mediator kinase inhibition further activates super-enhancer-associated genes in AML

Pelish, H. E., Liau, B. B., Nitulescu, I. I., Tangpeerachaikul, A., Poss, Z. C., Da Silva, D. H., et al. (2015). Mediator kinase inhibition further activates super-enhancer-associated genes in AML. NATURE, 526(7572), 273-276. doi:10.1038/nature14904.

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 Creators:
Pelish, Henry E.1, Author
Liau, Brian B.1, Author
Nitulescu, Ioana I.1, Author
Tangpeerachaikul, Anupong1, Author
Poss, Zachary C.1, Author
Da Silva, Diogo H.1, Author
Caruso, Brittany T.1, Author
Arefolov, Alexander1, Author
Fadeyi, Olugbeminiyi1, Author
Christie, Amanda L.1, Author
Du, Karrie1, Author
Banka, Deepti1, Author
Schneider, Elisabeth V.2, Author              
Jestel, Anja1, Author
Zou, Ge1, Author
Si, Chong1, Author
Ebmeier, Christopher C.1, Author
Bronson, Roderick T.1, Author
Krivtsov, Andrei V.1, Author
Myers, Andrew G.1, Author
Kohl, Nancy E.1, AuthorKung, Andrew L.1, AuthorArmstrong, Scott A.1, AuthorLemieux, Madeleine E.1, AuthorTaatjes, Dylan J.1, AuthorShair, Matthew D.1, Author more..
Affiliations:
1external, ou_persistent22              
2Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565155              

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Free keywords: TRANSCRIPTION FACTORS; CDK7 INHIBITOR; CELL IDENTITY; GENOME; CANCER; LIGAND; GUIDELINES; ULTRAFAST; KNOWLEDGE; ALIGNMENT
 Abstract: Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes(1,2). BRD4 and CDK7 are positive regulators of SE-mediated transcription(3-5). By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA-sensitiveAML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6 (refs 6-8). The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML.

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Language(s): eng - English
 Dates: 2015
 Publication Status: Published in print
 Pages: 20
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000362399000051
DOI: 10.1038/nature14904
 Degree: -

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Title: NATURE
Source Genre: Journal
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Publ. Info: MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND : NATURE PUBLISHING GROUP
Pages: - Volume / Issue: 526 (7572) Sequence Number: - Start / End Page: 273 - 276 Identifier: ISSN: 0028-0836