HIPPO-YAP融合蛋白的细胞核定位已被认为与上脑室室管膜瘤的发生有关。然而，我们在这里意外发现，患者来源的YAP融合蛋白（YAP-MAMLD1和C11ORF95-YAP）的液-液相分离，而非细胞核定位，是神经祖细胞形成室管膜瘤的基础。突变和嵌合体实验表明，本质无序区域促进YAP融合蛋白向核状无膜凝体寡聚化。YAP融合蛋白与转录激活子GCN4的卷曲-卷曲结构域诱导寡聚化和核状无膜凝体形成，促进室管膜瘤形成。YAP-MAMLD1将转录因子和共激活子（包括BRD4、MED1和TEAD）浓缩在凝体中，同时排除转录抑制性PRC2，并诱导促进转录和致癌编程的长程增强子-启动子相互作用。阻断凝体介导的转录共激活子活性可抑制肿瘤发生，表明液相分离对YAP融合蛋白致癌活性在室管膜瘤中发挥至关重要的作用。包含本质无序区域特征的YAP融合在人类肿瘤中很常见，因此核状无膜凝体可能成为治疗YAP融合引发癌症的靶点。© 2023年。作者（们）独家授权Springer Nature Limited。

Nuclear localization of HIPPO-YAP fusion proteins has been implicated in supratentorial ependymoma development. Here, unexpectedly, we find that liquid-liquid phase separation, rather than nuclear localization, of recurrent patient-derived YAP fusions, YAP-MAMLD1 and C11ORF95-YAP, underlies ependymoma tumourigenesis from neural progenitor cells. Mutagenesis and chimaera assays demonstrate that an intrinsically disordered region promotes oligomerization of the YAP fusions into nuclear, puncta-like, membrane-less condensates. Oligomerization and nuclear condensates induced by YAP fusion with a coiled-coil domain of transcriptional activator GCN4 also promote ependymoma formation. YAP-MAMLD1 concentrates transcription factors and co-activators, including BRD4, MED1 and TEAD, in condensates while excluding transcriptional repressive PRC2, and induces long-range enhancer-promoter interactions that promote transcription and oncogenic programmes. Blocking condensate-mediated transcriptional co-activator activity inhibits tumourigenesis, indicating a critical role of liquid phase separation for YAP fusion oncogenic activity in ependymoma. YAP fusions containing the intrinsically disordered region features are common in human tumours, suggesting that nuclear condensates could be targeted to treat YAP-fusion-induced cancers.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.