A mouse model of MYCN-driven retinoblastoma reveals MYCN-independent tumor reemergence
Nan Wu, … , Charles G. Eberhart, David MacPherson
Nan Wu, … , Charles G. Eberhart, David MacPherson
Published February 6, 2017
Citation Information: J Clin Invest. 2017;127(3):888-898. https://doi.org/10.1172/JCI88508.
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Research Article Genetics Oncology

A mouse model of MYCN-driven retinoblastoma reveals MYCN-independent tumor reemergence

Abstract

The most frequent focal alterations in human retinoblastoma are mutations in the tumor-suppressor gene retinoblastoma (RB) and amplification of the oncogene MYCN. Whether MYCN overexpression drives retinoblastoma has not been assessed in model systems. Here, we have shown that Rb inactivation collaborates strongly with MYCN overexpression and leads to retinoblastoma in mice. Overexpression of human MYCN in the context of Rb inactivation increased the expression of MYC-, E2F-, and ribosome-related gene sets, promoted excessive proliferation, and led to retinoblastoma with anaplastic changes. We then modeled responses to MYCN-directed therapy by suppressing MYCN expression in MYCN-driven retinoblastomas. Initially, MYCN suppression led to proliferation arrest and partial tumor regression with loss of anaplasia. However, over time, retinoblastomas reemerged, typically without reactivation of human MYCN or amplification of murine Mycn. A subset of returning retinoblastomas showed genomic amplification of a Mycn target gene encoding the miR cluster miR-17~92, while most retinoblastomas reemerged without clear genetic alterations in either Mycn or known Mycn targets. This Rb/MYCN model recapitulates key genetic driver alterations seen in human retinoblastoma and reveals the emergence of MYCN independence in an initially MYCN-driven tumor.

Authors

Nan Wu, Deshui Jia, Breanna Bates, Ryan Basom, Charles G. Eberhart, David MacPherson

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Figure 5

MYCN-independent retinoblastomas emerge in the absence of DOX.

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MYCN-independent retinoblastomas emerge in the absence of DOX. (A) BrdU...
(A) BrdU analysis showing regions with extensive proliferation in Rb/TET-MYCN retinae in the DOX-OFF condition 27 days after DOX removal, while other regions were nonproliferative. Black scale bar: 500 μm; white scale bars: 25 μm. Five of twelve eyes examined showed pockets of proliferation, with one section examined per eye. (B) Histogram showing the proportion of eyes with no tumor regression upon DOX removal, with regression but no regrowth, and with regression followed by DOX-independent tumor regrowth. (C) Photographs showing tumor regression upon DOX removal and then reappearance in the anterior chamber of the eye in 2 animals. (D) BrdU analysis showing a high proliferation rate in DOX-independent returned tumor. Scale bars: 50 μm. (E) Kaplan-Meier curves showing the time to development of late-stage retinoblastoma filling the eye. Rb/TET-MYCN mice were either maintained continuously on DOX (n = 17), or had DOX removed from their diet when the retinoblastoma was first externally visible in the eye (n = 42), usually with tumor evident in the anterior chamber. The P value shown was determined by log-rank test.