在胚胎发育过程中观察到的细胞命运转变涉及三维基因组组织的变化，这提供了适当的谱系特异性。是否类似的事件发生在肿瘤细胞中并有助于癌症演变仍未深入探讨。我们在儿童肿瘤尤文肉瘤中模拟了这个过程，并调查了与致癌融合蛋白EWS-FLI1相关的高分辨率环和大规模核构象变化。我们展示了肿瘤细胞中染色质相互作用主要由以EWS-FLI1结合位点为中心的高度连接的环状枢纽所支配，这直接控制了连接增强子和启动子的活性，以建立致癌表达程序。相反，EWS-FLI1消耗导致这些环状网络的解体和广泛的核再组织，通过建立新的环状模式和大规模区域配置，匹配了间充质干细胞中观察到的那些，这是尤文肉瘤祖细胞的候选。我们的数据表明，癌细胞核组织的主要建筑特征可以依赖于单一致癌基因，并可以很容易地逆转以重新建立潜在分化程序。

Cell fate transitions observed in embryonic development involve changes in three-dimensional genomic organization that provide proper lineage specification. Whether similar events occur within tumor cells and contribute to cancer evolution remains largely unexplored. We modeled this process in the pediatric cancer Ewing sarcoma and investigated high-resolution looping and large-scale nuclear conformation changes associated with the oncogenic fusion protein EWS-FLI1. We show that chromatin interactions in tumor cells are dominated by highly connected looping hubs centered on EWS-FLI1 binding sites, which directly control the activity of linked enhancers and promoters to establish oncogenic expression programs. Conversely, EWS-FLI1 depletion led to the disassembly of these looping networks and a widespread nuclear reorganization through the establishment of new looping patterns and large-scale compartment configuration matching those observed in mesenchymal stem cells, a candidate Ewing sarcoma progenitor. Our data demonstrate that major architectural features of nuclear organization in cancer cells can depend on single oncogenes and are readily reversed to reestablish latent differentiation programs.