Rheb1 promotes tumor progression through mTORC1 in MLL-AF9-initiated murine acute myeloid leukemia.
Rheb1 promotes tumor progression through mTORC1 in MLL-AF9-initiated murine acute myeloid leukemia.
复制标题
Rheb1 通过 mTORC1 在 MLL-AF9 引发的小鼠急性髓系白血病中促进肿瘤进展
DOI：
10.1186/s13045-016-0264-3
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发表时间：
2016-04-12
影响因子：
28.5
通讯作者：
Yuan W
中科院分区：
文献类型：
--
作者：
Gao Y;Gao J;Li M;Zheng Y;Wang Y;Zhang H;Wang W;Chu Y;Wang X;Xu M;Cheng T;Ju Z;Yuan W
背景磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt)/哺乳动物雷帕霉素靶点(MTOR)信号通路的结构性高激活与急性髓系白血病(AML)密切相关。虽然许多针对这些途径的抑制剂已经开发出来，但抗白血病效果并不像预期的那样强劲。作为PI3K/Akt和mTOR激酶之间分子联系的一部分，Rheb1在AML中的作用尚不清楚。本研究旨在探讨Rheb1在AML中的作用，并探讨Rheb1是否可能成为AML治疗的潜在靶点。采用逆转录病毒转导的方法建立AML小鼠模型。通过体外和体内研究，对白血病细胞特性和相关信号通路进行了剖析。基因芯片分析转录变化。用mTOR抑制剂和mTOR激活剂等分子试剂评价相关信号通路在小鼠模型中的作用。结果观察到Rheb1在AML患者中呈高表达，其水平的变化与患者的中位生存期有关。利用Rheb1缺陷的MLL-AF9小鼠AML模型，我们发现Rheb1缺失通过削弱LSC功能延长了AML小鼠的生存时间。此外，Rheb1基因缺失抑制了AML细胞的细胞周期进程，促进了细胞的凋亡。此外，虽然Rheb1基因缺失降低了急性髓系白血病细胞中mTORc1的活性，但额外的雷帕霉素处理进一步降低了mTORc1的活性并增加了Rheb1Δ/Δ急性髓系白血病细胞的凋亡率。结论Rheb1通过mTORc1信号通路促进Δ/Δ进展，针对Rheb1和mTOR的联合药物治疗可能对白血病有较好的治疗效果。
BackgroundThe constitutive hyper-activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways has frequently been associated with acute myeloid leukemia (AML). While many inhibitors targeting these pathways have been developed, the anti-leukemic effect was not as robust as expected. As part of the molecular link between PI3K/Akt and mTOR kinase, the role of Rheb1 in AML remains unexplored. Our study aims to explore the role of Rheb1 in AML and estimate whether Rheb1 could be a potential target of AML treatment.MethodsThe expressions ofRheb1and other indicated genes were analyzed using real-time PCR. AML mouse model was established by retrovirus transduction. Leukemia cell properties and related signaling pathways were dissected by in vitro and in vivo studies. The transcriptional changes were analyzed via gene chip analysis. Molecular reagents including mTOR inhibitor and mTOR activator were used to evaluate the function of related signaling pathway in the mouse model.ResultsWe observed that Rheb1 is overexpressed in AML patients and the change of Rheb1 level in AML patients is associated with their median survival. Using a Rheb1-deficient MLL-AF9 murine AML model, we revealed that Rheb1 deletion prolonged the survival of AML mice by weakening LSC function. In addition, Rheb1 deletion arrested cell cycle progression and enhanced apoptosis of AML cells. Furthermore, while Rheb1 deletion reduced mTORC1 activity in AML cells, additional rapamycin treatment further decreased mTORC1 activity and increased the apoptosis ofRheb1Δ/ΔAML cells. The mTOR activator 3BDO partially rescued mTORC1 signaling and inhibited apoptosis inRheb1Δ/ΔAML cells.ConclusionsOur data suggest that Rheb1 promotes AML progression through mTORC1 signaling pathway and combinational drug treatments targeting Rheb1 and mTOR might have a better therapeutic effect on leukemia.