Wu Nan, Jia Deshui, Bates Breanna, Basom Ryan, Eberhart Charles G, MacPherson David
J Clin Invest. 2017 Mar 1;127(3):888-898. doi: 10.1172/JCI88508. Epub 2017 Feb 6.
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.
人类视网膜母细胞瘤中最常见的局灶性改变是肿瘤抑制基因视网膜母细胞瘤（RB）的突变和癌基因MYCN的扩增。MYCN过表达是否驱动视网膜母细胞瘤尚未在模型系统中得到评估。在此，我们表明Rb失活与MYCN过表达强烈协同作用，并导致小鼠发生视网膜母细胞瘤。在Rb失活的背景下，人类MYCN的过表达增加了MYC、E2F和核糖体相关基因集的表达，促进了过度增殖，并导致具有间变改变的视网膜母细胞瘤。然后，我们通过抑制MYCN驱动的视网膜母细胞瘤中的MYCN表达来模拟对MYCN导向治疗的反应。最初，MYCN抑制导致增殖停滞和部分肿瘤消退，间变消失。然而，随着时间的推移，视网膜母细胞瘤再次出现，通常没有人类MYCN的重新激活或小鼠Mycn的扩增。一部分复发的视网膜母细胞瘤显示出编码miR簇miR - 17~92的Mycn靶基因的基因组扩增，而大多数视网膜母细胞瘤再次出现时，Mycn或已知Mycn靶标均无明显的基因改变。这种Rb/MYCN模型概括了人类视网膜母细胞瘤中所见的关键遗传驱动改变，并揭示了在最初由MYCN驱动的肿瘤中出现MYCN非依赖性的情况。
