title: Oncogenic MITF dysregulation in clear cell sarcoma: defining the MiT family of human cancers.
abstract: Clear cell sarcoma (CCS) harbors a pathognomonic chromosomal translocation fusing the Ewing's sarcoma gene (EWS) to the CREB family transcription factor ATF1 and exhibits melanocytic features. We show that EWS-ATF1 occupies the MITF promoter, mimicking melanocyte-stimulating hormone (MSH) signaling to induce expression of MITF, the melanocytic master transcription factor and an amplified oncogene in melanoma. Knockdown/rescue studies revealed that MITF mediates the requirement of EWS-ATF1 for CCS survival in vitro and in vivo as well as for melanocytic differentiation. Moreover, MITF and TFE3 reciprocally rescue one another in lines derived from CCS or pediatric renal carcinoma. Seemingly unrelated tumors thus employ distinct strategies to oncogenically dysregulate the MiT family, collectively broadening the definition of MiT-associated human cancers.
authors.affiliation: Melanoma Program in Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Davis
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Kim
authors.forename: Fatih
authors.initials: F
authors.lastname: Ozsolak
authors.forename: Hans R
authors.initials: HR
authors.lastname: Widlund
authors.forename: Orit
authors.initials: O
authors.lastname: Rozenblatt-Rosen
authors.forename: Scott R
authors.initials: SR
authors.lastname: Granter
authors.forename: Jinyan
authors.initials: J
authors.lastname: Du
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Denny
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Lessnick
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
mesh_terms: D051697:Activating Transcription Factor 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006609:High Mobility Group Proteins / Q000096:biosynthesis; D006801:Humans; D009074:Melanocyte-Stimulating Hormones / Q000502:physiology; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D034802:RNA-Binding Protein EWS / Q000235:genetics*; D000071701:Regulatory Factor X Transcription Factors; D055757:SOXE Transcription Factors; D018227:Sarcoma, Clear Cell / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: C531110:ATF1 protein, human; D051697:Activating Transcription Factor 1; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D034802:RNA-Binding Protein EWS; D000071701:Regulatory Factor X Transcription Factors; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; C069203:TFE3 protein, human; D014157:Transcription Factors; D009074:Melanocyte-Stimulating Hormones