Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
Pathol Int. 2021 Oct;71(10):643-654. doi: 10.1111/pin.13142. Epub 2021 Jul 15.
Disease-specific gene fusions are reportedly major driver mutations in approximately 30% of bone and soft tissue sarcomas. Most fusion genes encode transcription factors or co-factors that regulate downstream target genes, altering cell growth, lineage commitment, and differentiation. Given the limitations of investigating their functions in vitro, the generation of mouse models expressing fusion genes in the appropriate cellular lineages is pivotal. Therefore, we generated a series of mouse models by introducing fusion genes into embryonic mesenchymal progenitors. This review describes mouse models of Ewing, synovial, alveolar soft part, and CIC-rearranged sarcomas. Furthermore, we describe the similarities between these models and their human counterparts. These models provide remarkable advantages to identify cells-of-origin, specific collaborators of fusion genes, angiogenesis key factors, or diagnostic biomarkers. Finally, we discuss the relationship between fusion proteins and the epigenetic background as well as the possible role of the super-enhancers.
据报道，特定于疾病的基因融合是约 30%的骨和软组织肉瘤中的主要驱动突变。大多数融合基因编码转录因子或共因子，它们调节下游靶基因，改变细胞生长、谱系决定和分化。鉴于体外研究其功能的局限性，在适当的细胞谱系中表达融合基因的小鼠模型的生成至关重要。因此，我们通过将融合基因引入胚胎间充质祖细胞中生成了一系列小鼠模型。本综述描述了尤文氏肉瘤、滑膜肉瘤、腺泡状软组织肉瘤和 CIC 重排肉瘤的小鼠模型。此外，我们还描述了这些模型与人类对应物之间的相似之处。这些模型提供了显著的优势，可以鉴定起源细胞、融合基因的特定协作因子、血管生成关键因素或诊断生物标志物。最后，我们讨论了融合蛋白与表观遗传背景之间的关系以及超级增强子的可能作用。
