Foxo1和Shp1介导的合成性致死对NK/T细胞淋巴瘤糖酵解代谢的调控研究

In contrast to normal NK cells, NK/T-cell lymphoma is devoid of the expression of Shp1, which makes it difficult for precision targeted therapy. In our previous research of NK/T-cell lymphoma murine models, we found that both Foxo1 and Shp1 deficiencies in NK cells cause the loss of these cells in vivo, but either Foxo1 or Shp1 deficiency does not impair the survival of NK cells, so we assumed there is a synthetic lethality interaction between Foxo1 and Shp1 in NK cells, which might be a potential treatment for NK/T-cell lymphoma. Given that either Foxo1 or Shp1 deficiency enhances glycolysis, the synthetic lethality induced by Foxo1 and Shp1 deficiencies should be related to glycolysis changes. On the basis of previous data, we plan to explore the alterations and potential mechanism of activation induced death, metabolic products and protein molecules in glycolysis reactions after depleting Foxo1 and Shp1 in NK cells and NK-cell lymphoma in vitro, and the change of tumorigenecity and progress of NK-cell lymphoma after inducing Foxo1 and Shp1 deficiencies in vivo. This project is helpful for identifying the new mechanism of Foxo1 and Shp1 inducing synthetic lethality through glucose metabolism in NK cells, and provides a novel theoretical basis for exploiting synthetic lethality to treat Shp1-deficient NK/T-cell lymphoma via targeting Foxo1.

与正常NK细胞不同，NK/T细胞淋巴瘤表现为Shp1表达缺失，且难以就此实施靶向治疗。我们制备NK/T细胞淋巴瘤模型小鼠时发现同时敲除Foxo1和Shp1后体内NK细胞消失，而单独敲除Foxo1或Shp1不影响其存活，说明Foxo1和Shp1之间存在合成性致死作用，可能适合用于治疗NK/T细胞淋巴瘤。由于Foxo1或Shp1单独缺失均可促进糖酵解，因此Foxo1和Shp1同时缺失引起的合成性致死可能与糖酵解相关。本项目拟继续对Foxo1和Shp1缺失引起NK细胞和NK细胞淋巴瘤细胞因子活化诱导死亡、糖酵解反应中的代谢产物生成与相应调控蛋白的变化及机制，以及是否影响体内NK细胞淋巴瘤的成瘤性和进展进行深入研究。本项目研究结果有助于明确NK细胞及NK细胞淋巴瘤内Foxo1和Shp1缺失引起合成性致死的糖代谢机制，还有望为通过靶向Foxo1来治疗缺失Shp1的NK/T细胞淋巴瘤提供新的理论依据。

NK/T细胞淋巴瘤属于高度侵袭性和致死性的恶性淋巴瘤，发病机制尚未完全明了。我们最初认为Foxo1和Shp1之间存在着合成性致死效应，可被应用于NK细胞淋巴瘤治疗的探索研究。但是，经过反复检测，我们发现NKp46icre;Foxo1fl/fl和NKp46icre;Shp1fl/fl或者NKp46icre;Foxo1fl/fl;Shp1fl/fl等条件性敲除小鼠体内NK细胞实际并未完全消失。并且，我们还进一步发现无论单敲Foxo1、PTEN、Shp1和染色体13q14或者两两联合敲除这些基因，甚至敲除含Foxo1在内的三个基因，NK细胞正常存在，且均未发现有NK/T细胞淋巴瘤的发生。因此我们在随后的研究工作中调整了部分研究内容。临床工作中，晚期NK/T细胞淋巴瘤患者常伴有噬血细胞综合征，我们在对NK/T细胞淋巴瘤的研究工作中，对淋巴瘤合并噬血细胞综合征与不合并噬血细胞综合征患者的血清进行了差异蛋白组学筛选，发现可溶性VSIG4高表达于淋巴瘤合并噬血细胞综合征患者的外周血清中，经过多中心临床样品验证，可溶性VSIG4可被应用于淋巴瘤合并噬血细胞综合征的诊断。噬血细胞综合征患者的临床诊断，是血液系统疾病中的难点和热点问题之一。因而，发掘出诊断噬血细胞综合征的特异标志物对于认识、鉴别和确诊噬血细胞综合征患者，具有重要的临床应用价值。