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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A Drosophila model of the rhabdomyosarcoma initiator PAX7-FKHR
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A Drosophila model of the rhabdomyosarcoma initiator PAX7-FKHR

机译：横纹肌肉瘤引发剂PAX7-FKHR的果蝇模型

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Alveolar rhabdomyosarcoma (ARMS) is an aggressive myogenic-type tumor and a gain-of-function disease, caused by misexpres-sion of the PAX3-FKHR or PAX7-FKHR fusion oncoprotein from structurally rearranged chromosomes. PAX3-FKHR misexpressed in terminally differentiating mouse myofibers can cause rhabdomyosarcoma at a low frequency, suggesting that skeletal muscle is an ARMS tissue of origin. Because patterned muscle is widely viewed as irreversibly syncytial, questions persist, however, regarding this potential pathogenetic mechanism for ARMS tumor initiation. To further explore this issue, we generated transgenic Drosophila lines that conditionally express human PAX-FKHR. Here we show that PAX7-FKHR causes nucleated cells to form and separate from syncytial myofibers, which then spread to nonmuscular tissue compartments, including the central nervous system, and that wild-type PAX3 demonstrates similar potential. We further show that Ras, which is known to interfere with the differentiation of myogenic cells, genetically interacts with PAX7-FKHR: constitu-tively activated Ras enhances PAX7-FKHR phenotypes, whereas loss-of-function ras alleles dominantly suppress PAX7-FKHR activity, including rescue of lethality. These results show that PAX-FKHR can drive the generation of discrete nucleated cells from differentiated myofibers in vivo, argue for syncytial muscle as an ARMS tissue of origin, and demonstrate that Drosophila provides a powerful system to screen for genetic modifiers of PAX-FKHR.
机译：肺泡横纹肌肉瘤（ARMS）是一种侵袭性的成肌型肿瘤，是功能性疾病，由PAX3-FKHR或PAX7-FKHR融合癌蛋白从结构重排染色体的错误表达引起。在终末分化的小鼠肌纤维中错误表达的PAX3-FKHR可以低频率引起横纹肌肉瘤，这表明骨骼肌是起源于ARMS的组织。由于人们普遍认为图案化的肌肉是不可逆的合胞体，因此关于ARMS肿瘤起始的潜在致病机制仍然存在疑问。为了进一步探讨这个问题，我们产生了有条件表达人PAX-FKHR的转基因果蝇品系。在这里，我们显示PAX7-FKHR导致有核细胞形成并与合胞体肌纤维分开，然后扩散到包括中枢神经系统在内的非肌肉组织区室，而野生型PAX3表现出相似的潜力。我们进一步显示，已知会干扰成肌细胞分化的Ras与PAX7-FKHR发生遗传相互作用：组成性激活的Ras增强PAX7-FKHR表型，而功能丧失的ras等位基因则主要抑制PAX7-FKHR活性。 ，包括挽救杀伤力。这些结果表明，PAX-FKHR可以在体内驱动分化的肌纤维生成离散的有核细胞，证明合胞体肌肉是ARMS的起源组织，并证明果蝇为筛选PAX-FKHR的遗传修饰剂提供了强大的系统。

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