骨髓间充质干细胞来源的S100A8对AML发生发展的作用及机制研究

Emerging evidence points to a role for the bone marrow microenvironment, especially the mesenchymal stem cell (MSC) as a driver of leukemia maintenance/progression. However, the underlying mechanism remains largely unexplored. Our previous study showed overexpression of S100A8 in MSC derived from AML mice model and AML patients. Moreover, S100A8-silenced MSCs showed a decrease in proliferative cells and increased expression of CXCL12 and SCF. Furthermore, the proliferation and colony formation capacity of AML cell was reduced when cocultured with S100A8-silenced MSC. These results indicate that S100A8 may regulate AML development by changing the microenvironment. In this study, we plan to investigate the role of S100A8 in regulating bone marrow microenvironment and AML development by coculturing AML with S100A8-silenced MSC and constructing MSC-specific S100A8 knockout leukemia mice model. This research will provide new insights into the importance of the bone marrow microenvironment for AML development, and lay the foundation for tackling leukemia from a different angle to improve current treatments.

骨髓微环境包括骨髓间充质干细胞（MSC）在急性髓系白血病（AML）的发生发展过程中起重要作用，但是，目前对MSC调控AML的具体分子机制所知并不多。我们的前期工作发现S100A8在小鼠及AML患者MSC中高表达。体外实验证明小鼠骨髓MSC中敲降S100A8，MSC增殖减少，细胞因子CXCL12、SCF表达上升，与之共培养的AML细胞增殖及集落形成能力下降。提示MSC来源的S100A8高表达可能重塑骨髓微环境并调控AML发生发展。本项目拟在体外培养AML患者骨髓MSC，敲降S100A8，与AML原代细胞或细胞系共培养，并在MSC特异的S100A8敲除小鼠基础上构建AML模型，从细胞和动物水平探讨S100A8对骨髓微环境和AML的作用，明确S100A8调控AML的分子机制，为寻找AML治疗新靶点提供理论依据。

骨髓微环境包括骨髓间充质干细胞（MSC）在急性髓系白血病（AML）的发生发展过程中起重要作用。但是，目前对MSC调控AML的具体分子机制所知并不多。我们通过体外MSC与AML细胞共培养发现白血病状态下S100A8表达显著升高。体外细胞实验利用慢病毒在MSC细胞中过表达S100A8，与AML细胞共培养；体内动物实验繁育MSC特异的S100A8敲除小鼠，构建MLL-AF9白血病动物模型，共同证明S100A8促进MSC细胞增殖，促进MSC向早期成骨细胞分化、抑制MSC向脂肪细胞分化，并导致细胞因子分泌谱改变，PGE2分泌升高。MSC来源S100A8促进白血病进展，S100A8缺失小鼠生存期缩短。S100A8促进AML细胞及白血病干细胞（LSC）增殖，LSC处于G0期细胞减少，白血病凋亡减少、对依托泊苷耐药增强。转录组测序发现MSC过表达激活白血病细胞PI3K/Akt通路。此外，S100A8促进照射和5-FU处理后的造血干祖细胞和髓系细胞的再生。说明S100A8是应激状态下造血恢复及白血病发展的关键因子。