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

Abstract

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.

Modeling the effect of the RB tumor suppressor on disease progression: dependence on oncogene network and cellular context

“…In particular, most tumors exhibit a combination of tumor-suppressor dysfunction coupled with oncogene activation. Such cooperation has long been analysed in the context of oncogenic transformation in fibroblastic models (Zhu et al, 1998;Groth et al, 2000;Mallette et al, 2004;MacPherson et al, 2007). However, the relative contribution and specificity of such events to existing tumor phenotypes has not been well delineated.…”

miR than meets the eye: Figure 1.

“…Although this finding needs to be confirmed in a larger set of retinoblastomas, it suggests that in human retinoblastomas, up-regulation of miR-17;92 is a common event that is usually achieved via transcriptional or post-transcriptional mechanisms. E2F activity is high in RB mutant cells such as retinoblastoma cells; in addition, the MYC oncogene is activated in a fraction of mouse and human retinoblastomas (Lee et al 1984;MacPherson et al 2007). Because miR-17;92 is a direct transcriptional target of both MYC and E2F1 (O'Donnell et al 2005;Sylvestre et al 2007;Woods et al 2007), the activation of these two oncogenic transcription factors may partially explain the upregulation of miR-17;92 levels in retinoblastoma cells.…”

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

“…The majority of cases of retinoblastoma overexpress Nmyc, and a small subset of these cases also harbors significant N-myc gene amplification (25)(26)(27). Although uncommon, N-myc amplification in retinoblastoma is independent of germline or somatic mutation of the retinoblastoma gene (RB1), and is associated with early onset (median age, 4.5 months), unilateral disease, and clinical aggressiveness (28).…”