title: NSD3-NUT fusion oncoprotein in NUT midline carcinoma: implications for a novel oncogenic mechanism.
abstract: NUT midline carcinoma (NMC) is an aggressive subtype of squamous cell carcinoma that typically harbors BRD4/3-NUT fusion oncoproteins that block differentiation and maintain tumor growth. In 20% of cases, NUT is fused to uncharacterized non-BRD gene(s). We established a new patient-derived NMC cell line (1221) and demonstrated that it harbors a novel NSD3-NUT fusion oncogene. We find that NSD3-NUT is both necessary and sufficient for the blockade of differentiation and maintenance of proliferation in NMC cells. NSD3-NUT binds to BRD4, and BRD bromodomain inhibitors induce differentiation and arrest proliferation of 1221 cells. We find further that NSD3 is required for the blockade of differentiation in BRD4-NUT-expressing NMCs. These findings identify NSD3 as a novel critical oncogenic component and potential therapeutic target in NMC.
  
  
  CONCLUSIONS
  The existence of a family of fusion oncogenes in squamous cell carcinoma is unprecedented, and should lead to key insights into aberrant differentiation in NMC and possibly other squamous cell carcinomas. The involvement of the NSD3 methyltransferase as a component of the NUT fusion protein oncogenic complex identifies a new potential therapeutic target.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital; cfrench@partners.org.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: French
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts;
authors.forename: Shaila
authors.initials: S
authors.lastname: Rahman
authors.affiliation: Department of Pathology, Brigham and Women's Hospital;
authors.forename: Erica M
authors.initials: EM
authors.lastname: Walsh
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts;
authors.forename: Simone
authors.initials: S
authors.lastname: Kühnle
authors.affiliation: Department of Pathology, Brigham and Women's Hospital;
authors.forename: Adlai R
authors.initials: AR
authors.lastname: Grayson
authors.affiliation: Bioinfo, Plantagenet, Ontario, Canada.
authors.forename: Madeleine E
authors.initials: ME
authors.lastname: Lemieux
authors.affiliation: Department of Pathology, Brigham and Women's Hospital;
authors.forename: Noam
authors.initials: N
authors.lastname: Grunfeld
authors.affiliation: Robert J. Tomsich Pathology & Laboratory Medicine Institute, Department of Molecular Genetics, Cleveland Clinic, and Lerner Research Institute, Cleveland, Ohio;
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York;
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Texas Health Science Center at Houston, Houston, Texas;
authors.forename: Songlin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California; and.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Venkatramani
authors.affiliation: Department of Pathology, Brigham and Women's Hospital;
authors.forename: Paola
authors.initials: P
authors.lastname: Dal Cin
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts;
authors.forename: Peter M
authors.initials: PM
authors.lastname: Howley
mesh_terms: D000293:Adolescent; D063646:Carcinogenesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D011495:Histone-Lysine N-Methyltransferase; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C000630260:NUTM1 protein, human; C432968:NSD3 protein, human