Wild-type ALK and activating ALK-R1275Q and ALK-F1174L mutations upregulate Myc and initiate tumor formation in murine neural crest progenitor cells.
Wild-type ALK and activating ALK-R1275Q and ALK-F1174L mutations upregulate Myc and initiate tumor formation in murine neural crest progenitor cells.
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DOI：
10.18632/oncotarget.2036
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发表时间：
2014-06-30
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影响因子：
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通讯作者：
Mühlethaler-Mottet A
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作者：
Montavon G;Jauquier N;Coulon A;Peuchmaur M;Flahaut M;Bourloud KB;Yan P;Delattre O;Sommer L;Joseph JM;Janoueix-Lerosey I;Gross N;Mühlethaler-Mottet A
间变性淋巴瘤激酶 (ALK) 基因在大多数神经母细胞瘤 (NB)（一种小儿神经嵴衍生胚胎肿瘤）中过度表达、突变或扩增。两种最常见的突变 ALK-F1174L 和 ALK-R1275Q 有助于小鼠模型中的 NB 肿瘤发生，并在致癌过程中与 MYCN 协同作用。然而，激活 ALK 突变或 ALK-wt 过表达在 NB 肿瘤发生中的确切作用需要进一步阐明。人 ALK-wt、ALK-F1174L 或 ALK-R1275Q 在小鼠神经嵴祖细胞 (NCPC)、MONC-1 或 JoMa1 中稳定表达，分别用 v-Myc 或他莫昔芬诱导型 Myc-ERT 永生化。 MONC-1亲代细胞原位植入裸鼠体内产生了多种肿瘤类型，如NB、骨/软骨肉瘤和未分化肿瘤，但由于v-Myc致癌活性，MONC-1-ALK-F1174L细胞仅产生未分化肿瘤。此外，我们的数据首次证明了 ALK-wt 转化能力，因为 JoMa1 细胞中的 ALK-wt 表达，同样的 ALK-F1174L 或 ALK-R1275Q，在缺乏外源 Myc-ERT 活性的情况下，足以诱导侵袭性和未分化的神经嵴细胞衍生肿瘤的形成，但不会驱动 NB 的发展。有趣的是，JoMa1-ALK 肿瘤及其衍生细胞系因 ALK 激活而上调 Myc 内源表达，并且 ALK 和 Myc 活性对于赋予肿瘤衍生 JoMa1 细胞体外致瘤特性是必要的。
The anaplastic lymphoma kinase (ALK) gene is overexpressed, mutated or amplified in most neuroblastoma (NB), a pediatric neural crest-derived embryonal tumor. The two most frequent mutations, ALK-F1174L and ALK-R1275Q, contribute to NB tumorigenesis in mouse models, and cooperate with MYCN in the oncogenic process. However, the precise role of activating ALK mutations or ALK-wt overexpression in NB tumor initiation needs further clarification. Human ALK-wt, ALK-F1174L, or ALK-R1275Q were stably expressed in murine neural crest progenitor cells (NCPC), MONC-1 or JoMa1, immortalized with v-Myc or Tamoxifen-inducible Myc-ERT, respectively. While orthotopic implantations of MONC-1 parental cells in nude mice generated various tumor types, such as NB, osteo/chondrosarcoma, and undifferentiated tumors, due to v-Myc oncogenic activity, MONC-1-ALK-F1174L cells only produced undifferentiated tumors. Furthermore, our data represent the first demonstration of ALK-wt transforming capacity, as ALK-wt expression in JoMa1 cells, likewise ALK-F1174L, or ALK-R1275Q, in absence of exogenous Myc-ERT activity, was sufficient to induce the formation of aggressive and undifferentiated neural crest cell-derived tumors, but not to drive NB development. Interestingly, JoMa1-ALK tumors and their derived cell lines upregulated Myc endogenous expression, resulting from ALK activation, and both ALK and Myc activities were necessary to confer tumorigenic properties on tumor-derived JoMa1 cells in vitro.