尤文肉瘤 (EwS) 是一种发生在骨骼和软组织中的癌症，通常由尤文肉瘤断点区域 1-Friend 白血病病毒整合 1 (EWS-FLI) 癌基因驱动。事实证明，EwS 转基因动物模型的实施很困难，很大程度上是由于 EWS-FLI 的高毒性。 EWS-FLI1FS 移码变体可以规避毒性，但仍然能够执行关键的致癌功能，为果蝇提供了第一个研究模型。然而，对表达全长、未经修饰的 EWS-FLI 的果蝇品系的探索仍然存在。在这里，我们表明 EWS-FLI1FS 的较低毒性归因于其移码 C 端肽引起的蛋白质水平降低，并报告了我们生成表达全长、未修饰的 EWS-FLI 的果蝇系的新策略。使用这些细胞系，我们发现 GGAA 微卫星 (GGAAμSats) 转录的上调在广泛的 EWS-FLI 蛋白浓度范围内呈现正线性相关。相反，与直觉相反，GGAAμSat 独立的转录组失调在同一范围内呈现相对较小的差异，表明 GGAAμSat 依赖性和独立的转录上调在改变 EWS-FLI 蛋白浓度方面呈现出不同的反应动力学。我们的结果支持了不同 EWS-FLI 表达水平的功能相关性，并提供了实验工具来研究果蝇中 EWS-FLI“高”和“低”状态的影响，这些状态已被报道并被怀疑对 EwS 很重要在人类中。

Ewing sarcoma (EwS) is a cancer that arises in the bones and soft tissues, typically driven by the Ewing's sarcoma breakpoint region 1-Friend leukemia virus integration 1 (EWS-FLI) oncogene. Implementation of genetically modified animal models of EwS has proved difficult largely owing to EWS-FLI's high toxicity. The EWS-FLI1FS frameshift variant that circumvents toxicity but is still able to perform key oncogenic functions provided the first study model in Drosophila. However, the quest for Drosophila lines expressing full-length, unmodified EWS-FLI remained open. Here, we show that EWS-FLI1FS's lower toxicity is owed to reduced protein levels caused by its frameshifted C-terminal peptide, and report new strategies through which we have generated Drosophila lines that express full-length, unmodified EWS-FLI. Using these lines, we have found that the upregulation of transcription from GGAA-microsatellites (GGAAμSats) presents a positive linear correlation within a wide range of EWS-FLI protein concentrations. In contrast, rather counterintuitively, GGAAμSats-independent transcriptomic dysregulation presents relatively minor differences across the same range, suggesting that GGAAμSat-dependent and -independent transcriptional upregulation present different kinetics of response with regards to changing EWS-FLI protein concentration. Our results underpin the functional relevance of varying EWS-FLI expression levels and provide experimental tools to investigate, in Drosophila, the effect of the EWS-FLI 'high' and 'low' states that have been reported and are suspected to be important for EwS in humans.