A novel mouse model of rhabdomyosarcoma underscores the dichotomy of MDM2-ALT1 function in vivo.
A novel mouse model of rhabdomyosarcoma underscores the dichotomy of MDM2-ALT1 function in vivo.
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DOI：
10.1038/onc.2017.282
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发表时间：
2018-01-04
期刊：
影响因子：
8
通讯作者：
Chandler DS
中科院分区：
文献类型：
--
作者：
Comiskey DF Jr;Jacob AG;Sanford BL;Montes M;Goodwin AK;Steiner H;Matsa E;Tapia-Santos AS;Bebee TW;Grieves J;La Perle K;Boyaka P;Chandler DS
癌基因MDM2的选择性剪接是对遗传毒性应激的反应。已知产生的主要剪接变异体mdm2-alt1可以激活P53通路，并阻止全长mdm2‘S对P53的负调控。尽管有这种明显的肿瘤抑制作用，MDM2-ALT1也与几种癌症有关。此外，MDM2-ALT1在儿童横纹肌肉瘤(RMS)的侵袭性转移疾病中也有表达，与组织学亚型无关。因此，我们建立了一个转基因MDM2-ALT1小鼠模型，这将使我们能够研究这种剪接变体对肿瘤发生发展的影响。在这里，我们展示了当MDM2-ALT1在p53基因缺失的小鼠中普遍表达时，它会导致包括RMS在内的梭形细胞肉瘤的发生率增加。我们的数据提供了证据，证明结构性MDM2-ALT1表达本身是一种致癌损伤，加剧了P53缺失诱导的肿瘤发生。相反，当MDM2-ALT1在纯合子野生型p53存在的情况下仅在B细胞中表达时，与对照小鼠(27%)相比，它导致显著增加的淋巴肿大(56%)。然而，这种表型只有在生命的后期(≥18个月)才能观察到。此外，对B细胞标记物的流式细胞仪分析显示，这些动物的脾中的B细胞数量与MDM2-ALT1相关。我们的数据表明，B细胞丢失是p53依赖的，是在野生型p53背景下持续表达MDM2-ALT1的反应。总体而言，我们的发现强调了MDM2剪接变异体作为p53依赖和p53非依赖性肿瘤发生的关键修饰物的重要性，强调了MDM2转录后调控在癌症中的复杂性。此外，表达MDM2-ALT1的p53缺失小鼠代表了一种新的融合阴性RMS小鼠模型。
Alternative splicing of the oncogene MDM2 is induced in response to genotoxic stress. MDM2-ALT1, the major splice variant generated, is known to activate the p53 pathway and impede full-length MDM2’s negative regulation of p53. Despite this perceptible tumor-suppressive role, MDM2-ALT1 is also associated with several cancers. Furthermore, expression of MDM2-ALT1 has been observed in aggressive metastatic disease in pediatric rhabdomyosarcoma (RMS), irrespective of histological subtype. Therefore, we generated a transgenic MDM2-ALT1 mouse model that would allow us to investigate the effects of this splice variant on the progression of tumorigenesis. Here we show when MDM2-ALT1 is ubiquitously expressed in p53 null mice it leads to increased incidence of spindle cell sarcomas, including RMS. Our data provide evidence that constitutive MDM2-ALT1 expression is itself an oncogenic lesion that aggravates the tumorigenesis induced by p53 loss. On the contrary, when MDM2-ALT1 is expressed solely in B cells in the presence of homozygous wild-type p53 it leads to significantly increased lymphomagenesis (56%) when compared to control mice (27%). However, this phenotype is observable only at later stages in life (≥18 months). Moreover, flow cytometric analyses for B cell markers revealed an MDM2-ALT1-associated decrease in the B cell population of the spleens of these animals. Our data suggest that the B cell loss is p53 dependent and is a response mounted to persistent MDM2-ALT1 expression in a wild-type p53 background. Overall our findings highlight the importance of an MDM2 splice variant as a critical modifier of both p53-dependent and p53-independent tumorigenesis, underscoring the complexity of MDM2 post-transcriptional regulation in cancer. Furthermore, MDM2-ALT1-expressing p53 null mice represent a novel mouse model of fusion-negative RMS.
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影响因子：
64.8
作者：
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通讯作者：
di Fagagna, Fabrizio d'Adda
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