EWS 融合癌蛋白是多种人类恶性肿瘤的基础，包括促纤维增生性小圆细胞瘤 (DSRCT)，这是一种由 EWS-WT1 融合蛋白驱动的侵袭性癌症。在这里，我们结合染色质占据和 3D 图谱来识别 EWS-WT1 依赖的基因调控网络和目标基因。我们证明 EWS-WT1 是一种强大的染色质激活剂，控制着原发肿瘤特征的致癌基因表达程序。与野生型 WT1 类似，EWS-WT1 有两种 DNA 结合域不同的亚型，我们发现它们具有不同的 DNA 结合特征，并且都是产生类似于原发性 DSRCT 的可行肿瘤所必需的。最后，我们确定了具有潜在治疗意义的候选 EWS-WT1 靶基因，包括 CCND1，其被临床批准的药物 Palbociclib 抑制可导致 DSRCT PDX 体内肿瘤负荷显着降低。总而言之，我们的研究确定了 DSRCT 中的基因调控程序和治疗漏洞，并提供了对 EWS-WT1 复杂致癌活性的机制理解。© 2024。作者。

EWS fusion oncoproteins underlie several human malignancies including Desmoplastic Small Round Cell Tumor (DSRCT), an aggressive cancer driven by EWS-WT1 fusion proteins. Here we combine chromatin occupancy and 3D profiles to identify EWS-WT1-dependent gene regulation networks and target genes. We show that EWS-WT1 is a powerful chromatin activator controlling an oncogenic gene expression program that characterizes primary tumors. Similar to wild type WT1, EWS-WT1 has two isoforms that differ in their DNA binding domain and we find that they have distinct DNA binding profiles and are both required to generate viable tumors that resemble primary DSRCT. Finally, we identify candidate EWS-WT1 target genes with potential therapeutic implications, including CCND1, whose inhibition by the clinically-approved drug Palbociclib leads to marked tumor burden decrease in DSRCT PDXs in vivo. Taken together, our studies identify gene regulation programs and therapeutic vulnerabilities in DSRCT and provide a mechanistic understanding of the complex oncogenic activity of EWS-WT1.© 2024. The Author(s).