T-ALL来源的骨髓基质细胞通过FGF2-FGFR2通路促进T-ALL增殖  

T-ALL derived bone marrow stromal stem cells promote T-ALL proliferation through the FGF2-FGFR2 pathway

作　　者：杨健 李敏 李越洋 田晨 YANG Jian;LI Min;LI Yueyang;TIAN Chen(Department of Surgical Oncology,Qingdao Central Cancer Hospital,Qingdao 266042,China;Department of Hematology,Tianjin Medical University Cancer Institute and Hospital,National Clinical Research Center for Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin Clinical Research Center for Cancer)

机构地区：[1]青岛市中心(肿瘤)医院肿瘤外科,266042 [2]天津医科大学肿瘤医院血液科,国家恶性肿瘤临床医学研究中心,天津市恶性肿瘤临床医学研究中心,天津市肿瘤防治重点实验室

出　　处：《天津医药》2025年第1期29-34,共6页Tianjin Medical Journal

基　　金：新疆维吾尔自治区自然科学基金资助项目(2022D01A09)。

摘　　要：目的探究骨髓基质细胞(BM-MSCs)对急性T淋巴细胞白血病(T-ALL)影响的作用机制,寻找靶向BMMSCs的有效治疗策略。方法构建Notch-1过表达诱导的T-ALL小鼠模型,分选T-ALL中BM-MSCs,与T-ALL细胞系建立体外共培养系统,检测共培养后T-ALL增殖能力变化。运用RNA测序技术寻找不同来源MSCs的差异表达基因,并用PCR验证。在小鼠体内注射BGJ398,检测肿瘤生长情况。结果与T-ALL来源的MSCs共培养后,T-ALL细胞的增殖能力显著增加。RNA测序结果显示,T-ALL来源的MSCs成纤维细胞生长因子2(FGF2)分泌增加,与TALL细胞上的成纤维细胞生长因子2受体(FGFR2)结合可激活T-ALL细胞中PI3K/AKT/mTOR信号通路。加入BGJ398阻断FGF2和FGFR2之间的相互作用可以抑制小鼠T-ALL肿瘤的生长。结论BM-MSCs可通过FGF2/FGFR2通路促进T-ALL肿瘤生长,阻断FGF2/FGFR2通路是克服BM-MSCs介导T-ALL进展的有效策略。Objective To elucidate the mechanistic role of bone marrow mesenchymal stromal cells(BM-MSCs)in T-cell acute lymphoblastic leukemia(T-ALL),and to find effective therapeutic strategies targeting BM-MSCs.Methods A TALL mouse model induced by Notch-1 overexpression was constructed.An in vitro co-culture system was established to investigate the proliferative capacity of T-ALL cells upon co-culturing with leukemia-derived MSCs.RNA sequencing was performed to identify key differentially expressed genes,which were further validated by PCR.BGJ398 was injected into mice to detect tumor growth.Results Co-culturing with T-ALL-derived MSCs resulted in a significant increase in T-ALL cell proliferation.RNA sequencing results revealed that the secretion of fibroblast growth factor 2(FGF2)from T-ALL-derived MSCs was increased,which binds to fibroblast growth factor 2 receptor(FGFR2)on T-ALL cells,activating the PI3K/AKT/mTOR signaling pathway.Blocking the interaction between FGF2 and FGFR2 using BGJ398 inhibited the growth of T-ALL tumors in mice.Conclusion BM-MSCs can promote T-ALL tumor growth through FGF2/FGFR2 pathway,and blocking FGF2/FGFR2 pathway is an effective strategy to overcome BM-MSCS-mediated T-ALL progression.

关 键 词：前体细胞淋巴母细胞白血病淋巴瘤 成纤维细胞生长因子2 细胞增殖 骨髓基质细胞 BGJ398 

分 类 号：R733.71[医药卫生—肿瘤]