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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 Article has an altmetric score of 1

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

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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 4

Sustained MYCN expression is initially required for retinoblastoma cell proliferation.

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Sustained MYCN expression is initially required for retinoblastoma cell ...
DOX removal in cell lines derived from Rb/TET-MYCN tumors led to (A) reduced MYCN protein expression on Western blotting and (B) proliferation impairment, as assessed by counting cells 1, 3, and 5 days after plating. Data were pooled from 3 independent experiments. (C) Western blot of histone extracts from 3 Rb/TET-MYCN cell lines showing reduced histone H3K9, H3K27, and H2A K5 acetylation (Ac) and increased H3K27 and H4K20 trimethylation (me3) upon removal of DOX from the media. Individual blots indicating equal loading are shown Supplemental Figure 4D. (D) DOX removal in vivo initially resulted in suppression of MYCN protein expression by day 4. (E) Immunohistochemical analysis shows decreased BrdU-positive cells and increased cleaved caspase 3 (CC3) levels 4 days after DOX removal. Black scale bars: 500 μm; white scale bars (insets): 25 μm. Plot shows quantification from 5 to 8 independent retinae per genotype. The P values were determined by Student's t test. (F) Photographs showing a mouse with retinoblastoma in the anterior chamber, compared with 49 days later when the tumor had regressed.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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