title: MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma.
abstract: NUT midline carcinoma (NMC) is an aggressive type of squamous cell carcinoma that is defined by the presence of BRD-NUT fusion oncogenes, which encode chimeric proteins that block differentiation and maintain tumor growth. BRD-NUT oncoproteins contain two bromodomains whose binding to acetylated histones is required for the blockade of differentiation in NMC, but the mechanisms by which BRD-NUT act remain uncertain. Here, we provide evidence that MYC is a key downstream target of BRD4-NUT. Expression profiling of NMCs shows that the set of genes whose expression is maintained by BRD4-NUT is highly enriched for MYC upregulated genes, and MYC and BRD4-NUT protein expression is strongly correlated in primary NMCs. More directly, we find that BRD4-NUT associates with the MYC promoter and is required to maintain MYC expression in NMC cell lines. Moreover, both siRNA knockdown of MYC and a dominant-negative form of MYC, omomyc, induce differentiation of NMC cells. Conversely, differentiation of NMC cells induced by knockdown of BRD4-NUT is abrogated by enforced expression of MYC. Together, these findings suggest that MYC is a downstream target of BRD4-NUT that is required for maintenance of NMC cells in an undifferentiated, proliferative state. Our findings support a model in which dysregulation of MYC by BRD-NUT fusion proteins has a central role in the pathogenesis of NMC.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Adlai R
authors.initials: AR
authors.lastname: Grayson
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Erica M
authors.initials: EM
authors.lastname: Walsh
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cameron
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Jernej
authors.initials: J
authors.lastname: Godec
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Todd
authors.initials: T
authors.lastname: Ashworth
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Ambrose
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Alexandra B
authors.initials: AB
authors.lastname: Aserlind
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Hongfang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Gerard
authors.initials: G
authors.lastname: Evan
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kluk
authors.affiliation: Harvard Medical School, Boston, MA.|Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: French
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C471990:BRD4-NUT fusion oncogene protein, human; C489427:MYC protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D016271:Proto-Oncogene Proteins c-myc