title: Notch activation as a driver of osteogenic sarcoma.
abstract: Osteogenic sarcoma (OS) is a deadly skeletal malignancy whose cause is unknown. We report here a mouse model of OS based on conditional expression of the intracellular domain of Notch1 (NICD). Expression of the NICD in immature osteoblasts was sufficient to drive the formation of bone tumors, including OS, with complete penetrance. These tumors display features of human OS; namely, histopathology, cytogenetic complexity, and metastatic potential. We show that Notch activation combined with loss of p53 synergistically accelerates OS development in mice, although p53-driven OS is not Rbpj dependent, which demonstrates a dual dominance of the Notch oncogene and p53 mutation in the development of OS. Using this model, we also reveal the osteoblasts as the potential sources of OS.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
authors.forename: Jianning
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Jiang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
authors.forename: Lichun
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Salvo
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
authors.forename: Huan-Chang
authors.initials: HC
authors.lastname: Zeng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Dawson
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
authors.forename: Terry K
authors.initials: TK
authors.lastname: Bertin
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
authors.forename: Pulivarthi H
authors.initials: PH
authors.lastname: Rao
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Donehower
authors.affiliation: Department of Pathology, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Gannon
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA; Howard Hughes Medical Institute, Houston, TX 77030, USA. Electronic address: blee@bcm.edu.
authors.forename: Brendan H
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010006:Osteoblasts / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1