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Cancer Cell. 2014 Sep 8;26(3):390-401. doi: 10.1016/j.ccr.2014.07.023.

Notch activation as a driver of osteogenic sarcoma.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
2
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.
3
Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
4
Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
5
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.
6
Department of Pathology, Baylor College of Medicine, One Baylor Plaza, R815, Houston, TX 77030, USA.
7
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.

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.

PMID:
25203324
PMCID:
PMC4159617
DOI:
10.1016/j.ccr.2014.07.023
[Indexed for MEDLINE]
Free PMC Article

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