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首页> 外文期刊>Oncogene >MYCN and ALKF1174L are sufficient to drive neuroblastoma development from neural crest progenitor cells
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MYCN and ALKF1174L are sufficient to drive neuroblastoma development from neural crest progenitor cells

机译：MYCN和ALKF1174L足以驱动神经rest祖细胞发展成神经母细胞瘤

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Neuroblastoma is an embryonal tumor with a heterogeneous clinical course. The tumor is presumed to be derived from the neural crest, but the cells of origin remain to be determined. To date, few recurrent genetic changes contributing to neuroblastoma formation, such as amplification of the MYCN oncogene and activating mutations of the ALK oncogene, have been identified. The possibility to model neuroblastoma in mice allows investigation of the cell of origin hypothesis in further detail. Here we present the evidence that murine neural crest progenitor cells can give rise to neuroblastoma upon transformation with MYCN or ALK~(F1174L). For this purpose we used JoMa1, a multipotent neural crest progenitor cell line, which is kept in a viable and undifferentiated state by a tamoxifen-activated c-Myc transgene (c-MycER~(T)). Expression of MYCN or ALK~(F1174L), one of the oncogenic ALK variants identified in primary neuroblastomas, enabled these cells to grow independently of c-MycER~(T) activity in vitro and caused formation of neuroblastoma-like tumors in vivo in contrast to parental JoMa1 cells and JoMa1 cells-expressing TrkA or GFP. Tumorigenicity was enhanced upon serial transplantation of tumor-derived cells, and tumor cells remained susceptible to the MYC-inhibitor, NBT-272, indicating that cell growth depended on functional MYCN. Our findings support neural crest progenitor cells as the precursor cells of neuroblastoma, and indicate that neuroblastomas arise as their malignant progeny.
机译：神经母细胞瘤是具有不同临床过程的胚胎肿瘤。推测肿瘤起源于神经rest，但起源细胞仍有待确定。迄今为止，几乎没有发现导致神经母细胞瘤形成的复发性遗传改变，例如MYCN癌基因的扩增和ALK癌基因的激活突变。在小鼠中建模神经母细胞瘤的可能性允许进一步详细研究起源细胞假说。在这里，我们提供了证据，证明鼠神经c祖细胞经MYCN或ALK〜（F1174L）转化后可引起神经母细胞瘤。为了这个目的，我们使用了JoMa1，一种多能神经c祖细胞系，它被他莫昔芬激活的c-Myc转基因（c-MycER〜（T））维持在存活且未分化的状态。在原发性神经母细胞瘤中鉴定出的一种致癌性ALK变体之一，MYCN或ALK〜（F1174L）的表达使这些细胞能够在体外独立于c-MycER〜（T）活性生长，并导致形成神经母细胞瘤样肿瘤。与亲本JoMa1细胞和表达Jork1细胞的TrkA或GFP相反。肿瘤来源细胞的系列移植后，致瘤性增强，并且肿瘤细胞仍然对MYC抑制剂NBT-272敏感，表明细胞生长取决于功能性MYCN。我们的发现支持神经rest祖细胞作为神经母细胞瘤的前体细胞，并表明神经母细胞瘤是其恶性子代。

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