title: Mediator kinase inhibition further activates super-enhancer-associated genes in AML.
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. BRD4 and CDK7 are positive regulators of SE-mediated transcription. 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-sensitive AML 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.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Henry E
authors.initials: HE
authors.lastname: Pelish
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Liau
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Ioana I
authors.initials: II
authors.lastname: Nitulescu
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Anupong
authors.initials: A
authors.lastname: Tangpeerachaikul
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Campus Box 596, Boulder, CO 80303, USA.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Poss
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Diogo H
authors.initials: DH
authors.lastname: Da Silva
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Brittany T
authors.initials: BT
authors.lastname: Caruso
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Arefolov
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Olugbeminiyi
authors.initials: O
authors.lastname: Fadeyi
authors.affiliation: Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Christie
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Karrie
authors.initials: K
authors.lastname: Du
authors.affiliation: Division of Hematology/Oncology, Children's Hospital, Boston, MA 02215, USA.
authors.forename: Deepti
authors.initials: D
authors.lastname: Banka
authors.affiliation: Proteros Biostructures GmbH, Bunsenstrasse 7a, D-82152 Martinsried, Germany.|Max-Planck-Institut für Biochemie, Am Kloperspitz 18, D-82152 Martinsried, Germany.
authors.forename: Elisabeth V
authors.initials: EV
authors.lastname: Schneider
authors.affiliation: Proteros Biostructures GmbH, Bunsenstrasse 7a, D-82152 Martinsried, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Jestel
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Zou
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Chong
authors.initials: C
authors.lastname: Si
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Campus Box 596, Boulder, CO 80303, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Ebmeier
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Cancer Biology and Genetics Program and Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Krivtsov
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Myers
authors.affiliation: Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kohl
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.affiliation: Cancer Biology and Genetics Program and Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.affiliation: Bioinfo, Plantagenet, Ontario K0B 1L0, Canada.
authors.forename: Madeleine E
authors.initials: ME
authors.lastname: Lemieux
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Campus Box 596, Boulder, CO 80303, USA.
authors.forename: Dylan J
authors.initials: DJ
authors.lastname: Taatjes
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Shair
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D056850:Cyclin-Dependent Kinase 8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics*; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D011083:Polycyclic Compounds / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases; D006576:Heterocyclic Compounds, 4 or More Rings; D009687:Nuclear Proteins; D011083:Polycyclic Compounds; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C568713:GSK1210151A; C531521:cortistatin A; C584437:CDK19 protein, human; C095686:CDK8 protein, human