PDF(Pubmed)
Abstract：
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.
摘要：
CIC：：DUX4肉瘤（CDS）是一种罕见但高度侵袭性的未分化小圆细胞肉瘤，由肿瘤抑制因子Capicua（CIC）和DUX4之间的融合驱动。目前,由于患者肿瘤样本和细胞系的缺乏,目前还没有有效的治疗方法,确定和转化更好的治疗方法的努力也受到限制.为了解决这个限制，我们生成了三种转基因CDS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，来自所有三种条件模型的嵌合小鼠均发展为自发性软组织肿瘤和播散性疾病。与双等位基因Cic功能和相邻loxP位点之间的距离无关，自发性（非Cre依赖性）肿瘤形成的渗透率是完全的。软组织和假定的转移性肿瘤的表征表明，它们始终表达CIC：：DUX4融合蛋白和许多疾病的下游标记物，将模型确定为CDS。此外,产生肿瘤来源的细胞系，并使用N末端HA表位标签进行ChIP-seq以映射融合基因特异性结合。这些数据集,以及配对的H3K27acChIP测序图，验证C::DUX4作为新形态转录激活因子。此外，它们与ETS家族转录因子是CDS核心调节电路的协同和冗余驱动因素的模型一致。
