B7-H1等表面免疫分子在白血病干细胞多能性维持中的作用和机制

Leukemia is one of the malignant tumors which severely endangers the health of the Human. Although bone marrow transplantation is considered as the most effective way to eradicate leukemia cells, it is hard to be carried out in some cases because of the difficulties in MHC matching. On the other side, there is some limitaions in the treatment of leukemia by chemotherapy. So far, many types of leukemias are still not effectively controlled by these routin treatments. Leukemia stem cells(LSCs), such as acute myeloid leukemia (AML) stem cells and acute lymphoid leukemia (ALL) stem cells, are considered as the source of the recurrence and drug resistance of leukemia. How to target LSCs is one of the difficult and hot spots. Recently，for the first time, we identified the immune inhibitory receptor for Angiopoietin-like proteins, LILRB2 (one of the member of LILR family), which can maintain the stemness of LSCs. These results indicate that those surface immune molecules, which are mainly expressed on the surface of immune cells including some receptors and ligands, may involve in the regulation of the stemness of LSCs. Meanwhile, our further preliminary data also shows that another immune inhibitory molecule, B7-H1, is expressed on LSCs and the expression level may be closely related to the survival of patients. According to this, this project will continue to screen and illuminate the expression and function of B7-H1, as well as some other surface immune molecules, such as other members of LILR family, in the regulation of stemness of LSCs. These studies will greately promote the development of the new strategy to eradicate the LSCs.

白血病是严重危害人类健康的恶性肿瘤之一，虽然骨髓移植是目前根治白血病的主要手段，但很多情况因骨髓配型困难而难以开展；另外，化疗药物的效果也有一定局限性，因而许多类型白血病还得不到有效控制。白血病干细胞（LSCs），如急性髓系白血病（AML）干细胞或急性淋巴细胞白血病（ALL）干细胞，被认为是白血病复发和耐药的根源，如何靶向LSCs是白血病治疗中的难点和热点。我们最近首次证实了血管生成素样蛋白的免疫抑制性受体LILRB2（LILR家族的一员），该受体能维持LSCs的多能性；这也提示表面免疫分子，即表达在细胞表面与免疫有关的受体或配体，可调控LSCs的多能性。我们后续的研究也提示另一免疫抑制性分子B7-H1可表达于LSCs，其表达强弱与临床预后联系密切。据此，本项目将筛选和剖析B7-H1及LILR家族成员等其他表面免疫分子在LSCs中的表达、作用和机制，这将可能极大推动根治白血病新策略的发展。

白血病是严重危害人类健康的恶性肿瘤之一，虽然骨髓移植和化疗是目前治疗（甚至根除）白血病的主要手段，但由于骨髓配型困难和化疗等药物的副作用，许多类型白血病得不到有效地控制。白血病干细胞（leukemia stem cells, LSCs）被认为是白血病复发和耐药的根源，如何靶向LSCs是白血病治疗中的难点和热点。通过抗体芯片以及候选基因库的筛选，我们证实了多个高表达于LSCs的表面免疫分子，包括B7-H1、B7-H4、CD244和JAM3等。进一步的研究表明显这些表面免疫分子可表达于临床急性髓系白血病（AML）病人标本，而且这些表面免疫分子表达的强弱和病人的预后具有非常密切的关联作用。利用转基因小鼠、白血病模型和病人标本等手段，我们阐明了这些分子的相关功能和分子机制：B7-H1通过JNK/Cyclin D2信号通路促进AML的发病进程；B7-H4通过抑制LSCs的自我更新，以及促进LSCs分化和细胞周期阻滞而在AML演变中发挥抑癌作用，且这一过程是通过PTEN/AKT/HIF-1A/RCOR2/RUNX1信号通路来实现；CD244和JAM3分别通过SHP-2/p27和LRP5/WNT/AKT/CCND1途径维持LSCs的自我更新能力并促进小鼠白血病的演变。.本项目所揭示的对LSCs干性具有重要调控作用的特异性表面分子及其相关机制，可为临床上使用相关手段（如功能性抗体）干预LSCs干性，进而治疗/根除白血病提供新方向，并具有重要的潜在应用价值。项目实施期间，已有3篇相关文章发表，另有1篇文章刚刚被JCI接收。团队获得面上/优青项目等基金资助5项（参与1项），培养博士研究生5名，培养优秀青年教师2名。