microRNA17~92簇在急性T淋巴细胞白血病糖皮质激素耐药中的分子机制研究

Glucocorticoids (GCs）can specifically induce apoptosis in malignant lymphoblasts and are thus pivotal in the treatment of lymphoid malignancies. Prednisone response in vivo is a strong and independent prognostic factor in childhood acute lymphoblastic leukemia (ALL). However, GC resistance is a therapeutic problem accounting for most of the treatment failures in T-ALL and remains a major obstacle to successful treatment. The exact molecular mechanisms of GC resistance remain poorly understood. Therefore, developing new targets which could reverse GC resistance to break through the bottleneck in ALL treatment is of fundamental importance in the further improvement of the outcome of T-ALL. In this study, we will use the GC-resistant T-ALL cell line CEM-C1-15 (CEM-C1) and its sister cell line, GC-sensitive CEM-C7-14 (CEM-C7) to be the research objects. We want to study microRNA 17~92 could regulate NOTCH1 in T-ALL and the role of cross-talk between anti-apoptotic PI3K/Akt and NF-signal pathway and pro-apoptotic GC-GR/p38-MAPK singal pathway, in order to reveal the molecular pathogenesis of microRNA 17~92 in glucocorticoid resisitance of T-ALL. So, we hope that the study result will be to provide a new thought about reverse GC resistance lymphoblasts in treatment for T-ALL patients.

糖皮质激素（GC）可以抑制急性淋巴细胞白血病（ALL）细胞的增殖，并诱导其凋亡，是治疗小儿ALL的里程碑式药物，同时，ALL细胞对GC的敏感性是决定其预后的一项强烈的、具有独立意义的指标。而T-ALL细胞GC耐药是导致儿童ALL治疗失败的主要原因之一，寻找能够协同逆转GC耐药的靶点或靶向药物是进一步提高儿童T-ALL治愈率的临床亟待解决的问题。本课题以小儿GC耐药细胞株（CEM-C1）及GC敏感细胞株（CEM-C7）为研究对象，通过研究micro RNA 17~92对T-ALL细胞NOTCH1的调控作用，进而介导抗凋亡的PI3K/AKT及NF-kB信号路径与促凋亡的GC-GR/p38-MAPK/Bim信号路径的相关作用（Cross-talk），揭示micro RNA 17~92 在T-ALL GC耐药中的分子机理，从而为探索逆转T-ALL细胞GC耐药提供一条新的思路和新的治疗靶点。

儿童急性淋巴细胞白血病（ALL）对糖皮质激素（GC）的敏感性与其预后密切相关。约15~30%的ALL患儿对GC原发耐药，在复发ALL病例中，GC耐药更是高达70%。因此，克服ALL细胞GC耐药是进一步提高儿童ALL治愈率亟待解决的问题。本课题对2009年1月至2014年3月在四川大学华西第二医院采用中国儿童白血病协作组2008方案（CCLG-ALL-2008）规范性分型治疗的424例ALL患儿的临床资料和疗效进行回顾性总结，预期5年OS率为（80.5±2.4）%，EFS率为（68.1±2.7）%，累积复发率（18.9±2.5）%。复发的ALL患儿具有中位发病年龄明显大，泼尼松敏感试验不敏感率高，第15天诱导缓解率低，外周血白细胞计数明显增高等临床特征。进一步以ALL细胞株为研究对象，通过荧光定量PCR、瞬时转染、细胞凋亡、信号通路研究等方法，发现与GC敏感的CEM-C7细胞相比，GC耐药的CEM-C1细胞高表达miRNA-92a，同时存在NOTCH1信号路径的高度活化，在转染miRNA-92a抑制剂后可抑制miRNA-92a的表达和NOTCH1信号路径的活化，进而抑制细胞内抗凋亡的PI3K/Akt及NF-B信号路径的活化，上调促凋亡的GC-GR/p38-MAPK/Bim信号路径，从而逆转CEM-C1对GC的耐药性，从而揭示miRNA-92a可能为GC耐药的儿童T-ALL提供新的治疗靶点。