c-MYC is an important driver of high-risk neuroblastoma. A lack of c-MYC–driven genetically engineered mouse models (GEMM) has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and to develop effective therapies. Here, we showed that conditional c-MYC induction via Cre recombinase driven by a tyrosine hydroxylase (Th) promoter led to a preponderance of PDX1+ somatostatinoma, a type of pancreatic neuroendocrine tumor (PNET). However, c-MYC activation via an improved Cre recombinase driven by a dopamine β-hydroxylase (Dbh) promoter resulted in neuroblastoma development. The c-MYC murine neuroblastoma tumors recapitulated the pathologic and genetic features of human neuroblastoma and responded to anti-GD2 immunotherapy and DFMO, an FDA-approved inhibitor targeting the MYC transcriptional target ODC1. Thus, c-MYC overexpression results in different but related tumor types depending on the targeted cell. The GEMMs represent valuable tools for testing immunotherapies and targeted therapies for these diseases.

中文翻译：

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不同儿茶酚胺能细胞中 c-MYC 的条件性激活驱动神经母细胞瘤或生长抑素瘤的发展


c-MYC 是高危神经母细胞瘤的重要驱动因素。缺乏 c-MYC 驱动的基因工程小鼠模型 （GEMM） 阻碍了更好地了解神经母细胞瘤肿瘤发生机制和开发有效疗法的能力。在这里，我们表明，由酪氨酸羟化酶 （Th） 启动子驱动的 Cre 重组酶的条件 c-MYC 诱导导致 PDX1 + 生长抑素瘤（一种胰腺神经内分泌肿瘤 （PNET））的优势。然而，由多巴胺 β-羟化酶 （Dbh） 启动子驱动的改进的 Cre 重组酶激活 c-MYC 导致神经母细胞瘤的发展。c-MYC 小鼠神经母细胞瘤肿瘤概括了人神经母细胞瘤的病理和遗传学特征，并对抗 GD2 免疫疗法和 DFMO（一种 FDA 批准的靶向 MYC 转录靶标 ODC1 的抑制剂）有反应。因此，c-MYC 过表达会导致不同但相关的肿瘤类型，具体取决于目标细胞。GEMM 代表了测试这些疾病的免疫疗法和靶向疗法的宝贵工具。