Cell-cycle dependent expression of a translocation-mediated fusion oncogene mediates checkpoint adaptation in rhabdomyosarcoma.
Cell-cycle dependent expression of a translocation-mediated fusion oncogene mediates checkpoint adaptation in rhabdomyosarcoma.
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DOI：
10.1371/journal.pgen.1004107
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发表时间：
2014-01
期刊：
影响因子：
4.5
通讯作者：
Keller C
中科院分区：
文献类型：
--
作者：
Kikuchi K;Hettmer S;Aslam MI;Michalek JE;Laub W;Wilky BA;Loeb DM;Rubin BP;Wagers AJ;Keller C
横纹肌肉瘤是儿童最常见的软组织肉瘤。大多数横纹肌肉瘤福尔斯属于两个生物学上不同的亚组之一，以泡状或胚胎组织学为代表。肺泡亚型携带易位介导的PAX3：FOXO1A融合基因，预后极差。然而，肿瘤细胞具有融合基因的异质性表达。使用条件遗传小鼠模型以及人类肿瘤细胞系，我们表明，Pax3：Foxo1a表达是丰富的G2和触发的转录程序有利于检查点适应应激条件下，如辐射在体外和体内。Pax3：Foxo1a还使肿瘤细胞对临床上确立的化疗药物和新兴的分子靶向药物耐受。因此，令人惊讶的动态调节Pax3：Foxo1a基因座是一个范例，具有重要意义的方式，其中癌基因在癌细胞中建模。罕见的儿童癌症可以成为从中发现重要新原则的范例。儿童肌肉癌横纹肌肉瘤也不例外，这是1969年Li和Fraumeni博士最初描述的一种综合征的焦点，现在已知通常由潜在的p53肿瘤抑制因子功能丧失引起。在我们的研究中，使用条件遗传小鼠模型的腺泡状横纹肌肉瘤与人类肿瘤细胞系，我们已经发现，表达水平的易位介导的融合基因，Pax3：Foxo1a，是动态的，并在细胞周期的变化。我们的研究支持Pax3：Foxo1a促进酵母相关的检查点适应过程中的压力，如辐射。我们的研究更广泛的意义是，远端顺式元件（DNA的启动子影响区域）可能是至关重要的，以充分了解癌症相关易位的功能。
Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in childhood. Most rhabdomyosarcoma falls into one of two biologically distinct subgroups represented by alveolar or embryonal histology. The alveolar subtype harbors a translocation-mediated PAX3:FOXO1A fusion gene and has an extremely poor prognosis. However, tumor cells have heterogeneous expression for the fusion gene. Using a conditional genetic mouse model as well as human tumor cell lines, we show that that Pax3:Foxo1a expression is enriched in G2 and triggers a transcriptional program conducive to checkpoint adaptation under stress conditions such as irradiation in vitro and in vivo. Pax3:Foxo1a also tolerizes tumor cells to clinically-established chemotherapy agents and emerging molecularly-targeted agents. Thus, the surprisingly dynamic regulation of the Pax3:Foxo1a locus is a paradigm that has important implications for the way in which oncogenes are modeled in cancer cells. Rare childhood cancers can be paradigms from which important new principles can be discerned. The childhood muscle cancer rhabdomyosarcoma is no exception, having been the focus of the original 1969 description by Drs. Li and Fraumeni of a syndrome now know to be commonly caused by underlying p53 tumor suppressor loss-of-function. In our studies using a conditional genetic mouse model of alveolar rhabdomyosarcoma in conjunction with human tumor cell lines, we have uncovered that the expression level of a translocation-mediated fusion gene, Pax3:Foxo1a, is dynamic and varies during the cell cycle. Our studies support that Pax3:Foxo1a facilitate the yeast-related process of checkpoint adaptation under stresses such as irradiation. The broader implication of our studies is that distal cis elements (promoter-influencing regions of DNA) may be critical to fully understanding the function of cancer-associated translocations.
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