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  • The EMBO Journal (2007) 26, 784 - 794
  • doi:10.1038/sj.emboj.7601515

Published online: 18 January 2007

Murine bilateral retinoblastoma exhibiting rapid-onset, metastatic progression and N-myc gene amplification

David MacPherson1, Karina Conkrite1, Mandy Tam2, Shizuo Mukai3, David Mu4 and Tyler Jacks2,5

  1. Department of Embryology, Carnegie Institution, Baltimore, MD, USA
  2. Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
  3. Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, MA, USA
  4. Human Cancer Genome Center, Cold Spring Harbor Laboratory, Woodbury, NY, USA
  5. Howard Hughes Medical Institute, Chevy Chase, MD, USA

Correspondence to:

David MacPherson, Department of Embryology, Carnegie Institution, 3520 San Martin Drive, Baltimore, MD 21218, USA. Tel.: +1 410 246 3084; Fax: +1 410 243 6311; E-mail: macpherson@ciwemb.edu

Received 11 August 2006; Accepted 28 November 2006

Human retinoblastoma is a pediatric cancer initiated by RB gene mutations in the developing retina. We have examined the origins and progression of retinoblastoma in mouse models of the disease. Retina-specific inactivation of Rb on a p130-/- genetic background led to bilateral retinoblastoma with rapid kinetics, whereas on a p107-/- background Rb mutation caused predominantly unilateral tumors that arose with delayed kinetics and incomplete penetrance. In both models, retinoblastomas arose from cells at the extreme periphery of the murine retina. Furthermore, late retinoblastomas progressed to invade the brain and metastasized to the cervical lymph nodes. Metastatic tumors lacking Rb and p130 exhibited chromosomal changes revealed by representational oligonucleotide microarray analysis including high-level amplification of the N-myc oncogene. N-myc was found amplified in three of 16 metastatic retinoblastomas lacking Rb and p130 as well as in retinoblastomas lacking Rb and p107. N-myc amplification ranged from 6- to 400-fold and correlated with high N-myc-expression levels. These murine models closely resemble human retinoblastoma in their progression and secondary genetic changes, making them ideal tools for further dissection of steps to tumorigenesis and for testing novel therapies.

  • Keywords:

    • N-myc,
    • p107,
    • p130,
    • retinoblastoma,
    • ROMA