套细胞淋巴瘤（mantle cell lymphoma, MCL)对现有治疗方法不敏感，预后差、中位生存时间仅3－5年。系统深入地阐明MCL的致病机制，寻找可用于药物靶点的关键异变基因及信号通路是治愈MCL的根本途径。我们的前期研究发现微小RNA（miR）-17-92在MCL细胞中的表达水平明显提高，并与患者的生存密切相关。体外和体内实验均显示miR-17-92的高表达能促进肿瘤细胞增殖并增强肿瘤抵抗化疗诱导的凋亡。本课题我们将利用已建立的多种小鼠移植瘤模型和细胞分子生物学技术，从三方面研究MCL的致病机制及关键致病基因，并探索设计针对我国MCL患者的靶向治疗：（1）微小RNA（miR）-17-92对MCL癌细胞代谢及增殖的调控，（2）miR-17-92水平对MCL临床靶向治疗的指导意义，及（3）针对关键异变基因及信号通路靶向治疗的临床前期探讨。

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma and is considered incurable using current standard chemotherapy. Novel therapeutic strategies are critically needed for this disease. Our group has previously demonstrated that the microRNA (miR)-17-92 cluster is aberrantly up-regulated in a subset of primary MCL tumors and that its overexpression is associated with poor survival in MCL patients. Enforced overexpression of miR-17-92 in MCL cells promotes cell proliferation and inhibits chemotherapy-induced apoptosis. Conversely, knockdown of miR-17-92 in MCL suppresses tumor cell growth and sensitizes these cells to chemotherapy-induced apoptosis in vitro and in a xenograft/SCID MCL mouse model. We demonstrated that miR-17-92 targets several negative regulators of the PI3K/AKT/mTOR pathway, including PTEN, PHLPP2 and TSC1. Recently, we found that miR-17-92 also directly targets several positive regulators of the AMPK pathway. Down-regulating these regulators inactivates AMPK signaling, which, together with the PI3K/AKT activation, induces the hyperactivation of mTOR Complex 1 (mTORC1). More importantly, we discovered that MCL cells overexpressing miR-17-92 are more susceptible to mTOR inhibitors, such as Temsirolimus, than those with lower miR-17-92 expression, which, conversely, have higher ERK activity. These findings suggest that MCL may actually consist of two different subgroups, each with distinct oncogenic pathway activation. We hypothesize that miR-17-92 is a biomarker for predicting better clinical response to mTOR inhibitors, and that MCL with low miR-17-92 expression may be susceptible to ERK pathway inhibition. We will (1) define the molecular mechanisms through which miR-17-92 induces hyperactivation of mTORC1 and promotes tumor cell proliferation and survival; (2) determine the specific oncogenic pathway activation in primary MCL tumors and the role of miR-17-92 as a biomarker for predicting the clinical response in MCL patients treated with mTOR inhibitors; and (3) determine the efficacy and mechanisms of targeting miR-17-92-low MCL tumors with specific ERK pathway inhibitors. The proposal will investigate oncogenic pathways not previously linked to miR-17-92 and provide new insights into miR-17-92-associated lymphomagenesis. The study will investigate the therapeutic potential for targeting MCL tumors based on the specific oncogenic pathway that is aberrantly activated and the intriguing preliminary finding that MCL may contain two molecularly defined subgroups with distinct activated oncogenic pathways. The study will therefore significantly advance our understanding of the molecular mechanisms of lymphomagenesis and has the potential to significantly impact treatment of MCL patients.

套细胞淋巴瘤（mantle cell lymphoma, MCL)对现有治疗方法不敏感，预后差、中位生存时间仅3－5 年。系统深入地阐明MCL 的致病机制，寻找可用于药物靶点的关键异变基因及信号通路是治愈MCL 的根本途径。我们在该研究中发现微小RNA（miR）-17-92 在MCL 细胞中的表达水平明显提高，并与患者的生存密切相关。体外和体内实验均显示miR-17-92 的高表达能促进肿瘤细胞增殖并增强肿瘤抵抗化疗诱导的凋亡。进一步研究显示实miRNA-17~92 能通过下调LKB1-AMPK-TSC 通路若干蛋白的表达抑制该通路活性，从而活化mTORC1，促进肿瘤细胞蛋白合成及增殖。此外，该研究还发现miRNA-17~92 的表达水平可作为预测临床mTORC1 抑制剂治疗敏感性的一个生物指标。