骨肉瘤（Osteosarcoma,OS）恶性度高，发病机制不明，缺乏明确分子分型及有效靶向治疗策略。课题组前期通过多组学测序分析发现OS中具有高频H3F3A-G34W突变，且突变型OS染色体稳定性和基因表达谱较野生型差异显著，在突变型OS原代细胞中敲除G34W可显著抑制细胞增殖，且G34W突变型细胞对HDAC抑制剂高度敏感。故提出假说：G34W突变型可能是一种新OS分子亚型，而HDAC可能成为它的治疗靶点。本项拟在前期基础上运用基因组学方法进一步探索根据G34W突变对OS进行分子分型的可行性并深入挖掘其细胞起源，还将利用原代肿瘤细胞和PDX模型，研究G34W突变在OS中的功能和分子机制，并结合肿瘤超级增强子分析进一步测试包括HDAC抑制剂在内的靶向治疗策略。本项目旨在揭示癌组蛋白突变H3F3A-G34W参与调控OS发生的分子机制，并寻找针对该突变的靶向治疗策略，为OS的治疗提供新思路。

Osteosarcoma (OS) with high malignancy and unclear pathogenesis is now lack of clear molecular typing and effective targeted therapies. Based on the preliminary multi-omics sequencing analysis by the research group, the H3F3A-G34W mutation was frequently identified in OS, and the mutant OS differed significantly from the wild-type OS in the chromosomal stability and gene expression profile. Also, knockdown of G34W in mutant OS primary cells could significantly inhibit cell proliferation, and G34W mutant cells were highly sensitive to HDAC inhibitors. Therefore, the hypothesis was proposed that G34W mutant may be a new OS molecular subtype whose therapeutic target may be HDAC. On this basis, this study will further explore the cell origin and the feasibility of OS molecular typing by G34W mutation based on genomics methods, and analyze the function and molecular mechanism of G34W in OS through primary tumor cells and the PDX model. Combined with the analysis of tumor super enhancers, this study will then test targeted therapeutic strategies with HDAC inhibitors included. Finally, this research aims to reveal the molecular mechanism of oncohistone H3F3A-G34W mutation in OS dysregulation, and find therapeutic strategies targeted at this mutation to provide new ideas for the OS treatment.