CIC::DUX4 sarcoma (CDS) is a rare but highly aggressive undifferentiated small round cell sarcoma driven by a fusion between the tumor suppressor Capicua (CIC) and DUX4. Currently, there are no effective treatments and efforts to identify and translate better therapies are limited by the scarcity of patient tumor samples and cell lines. To address this limitation, we generated three genetically engineered mouse models of CDS (Ch7CDS, Ai9CDS, and TOPCDS). Remarkably, chimeric mice from all three conditional models developed spontaneous soft tissue tumors and disseminated disease in the absence of Cre-recombinase. The penetrance of spontaneous (Cre-independent) tumor formation was complete irrespective of bi-allelic Cic function and the distance between adjacent loxP sites. Characterization of soft tissue and presumed metastatic tumors showed that they consistently expressed the CIC::DUX4 fusion protein and many downstream markers of the disease credentialing the models as CDS. In addition, tumor-derived cell lines were generated and ChIP-seq was preformed to map fusion-gene specific binding using an N-terminal HA epitope tag. These datasets, along with paired H3K27ac ChIP-sequencing maps, validate CIC::DUX4 as a neomorphic transcriptional activator. Moreover, they are consistent with a model where ETS family transcription factors are cooperative and redundant drivers of the core regulatory circuitry in CDS.

CIC::DUX4 肉瘤 (CDS) 是一种罕见但高度侵袭性的未分化小圆形细胞肉瘤，由肿瘤抑制基因 Capicua (CIC) 和 DUX4 之间的融合驱动。目前，还没有有效的治疗方法，并且由于患者肿瘤样本和细胞系的缺乏，识别和转化更好的疗法的努力受到限制。为了解决这一限制，我们生成了三种 CDS 基因工程小鼠模型（Ch7CDS、Ai9CDS 和 TOPCDS）。值得注意的是，在没有 Cre 重组酶的情况下，所有三种条件模型的嵌合小鼠都会产生自发性软组织肿瘤并传播疾病。无论双等位基因Cic功能和相邻 loxP 位点之间的距离如何，自发（不依赖 Cre 的）肿瘤形成的外显率都是完全的。软组织和假定的转移性肿瘤的特征表明，它们一致表达 CIC::DUX4 融合蛋白和许多疾病下游标记物，从而证明该模型为 CDS。此外，还生成了肿瘤来源的细胞系，并进行了 ChIP-seq，以使用 N 端 HA 表位标签绘制融合基因特异性结合图谱。这些数据集以及配对的 H3K27ac ChIP 测序图谱验证了 CIC::DUX4 作为新形态转录激活剂。此外，它们与 ETS 家族转录因子是 CDS 核心调节电路的协作和冗余驱动程序的模型一致。