靶向mTORC2通路对MLL白血病干细胞的影响及机制研究

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中文摘要
异常的mTOR通路活化是包括急性白血病在内众多恶性肿瘤常见分子事件之一。申请者前期研究发现,敲除mTORC2重要组份Rictor打破了MLL白血病干细胞的静息状态导致LSCs耗竭,提示Rictor可能在调控MLL白血病LSCs干性中起关键作用。为进一步揭示分子机制,运用MLL-AF6基因条件性敲入小鼠模型,明确Rictor敲除对MLL白血病恶性进程的影响;我们还发现,Rictor敲除导致MLL LSCs的mTORC1通路反应性活化,进入细胞周期并耗竭,但也引起FoxO3a活化,抑制Rictor缺失细胞mTORC1过度增高,对LSCs产生保护作用。基于前期基础,应用Rictor/FoxO3双敲小鼠模型,系统观察靶向Rictor和FoxO3a对MLL-AF9诱导的小鼠白血病模型发病、维持及LSCs的影响,探索Rictor-FoxO3a轴对维持MLL白血病LSCs静息状态及干性中的潜在调控作用。
英文摘要
Recent studies had found that the aberrant activation of mTOR pathway is one of the most common molecular events of many cancers including acute leukemia onset. Recently, we demonstrated that Loss of rictor disturbed the quiescence of leukemia stem cells (LSCs) in MLL-driven leukemia, resulted in exhaustion of LSCs in MLL leukemia. which indicated that Rictor was essential for the maintenance of MLL-driven leukemia by preventing LSCs from exhaustion. To explore the mechanism underlying the exhaustion of LSCs in MLL leukemia caused by Rictor deletion, we will use an established MLL-AF6 conditional gene knock-in mice model to define whether deletion of Rictor could affect maintaining of MLL-AML hematopoiesis. In our previous study, we also found Rictor depletion led to a reactive activation of mTORC1 signaling by facilitating the assembly of mTORC1. Hyperactivated mTORC1 signaling in turn drove LSCs into cycling, compromised the quiescence of LSCs and eventually exhausted their capacity to generate leukemia. Meanwhile, loss of Rictor had led to a reactive activation of FoxO3a in leukemia cells, which acts as negative feedback to restrain greater over-reactivation of mTORC1 activity and paradoxically protects leukemia cells from exhaustion. Based on previous studies, we will further evaluate the synergistic effects on the leukemogenesis, maintenance and stemness of MLL-driven Leukemia by Rictor/FoxO3 double deletion and to understand the underlying mechanism of a critical regulatory axis of Rictor-FoxO3a in the maintenance of MLL-driven leukemia.
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DOI:10.3389/fneur.2024.1334000
发表时间:2024-02
期刊:Frontiers in Neurology
影响因子:3.4
作者:Ningwen Li;Ruoxuan Zhang;Jue Wang;Xiaojian Zhu;Fankai Meng;Yang Cao;Gaoxiang Wang;Yang Yang-Yang
通讯作者:Ningwen Li;Ruoxuan Zhang;Jue Wang;Xiaojian Zhu;Fankai Meng;Yang Cao;Gaoxiang Wang;Yang Yang-Yang
DOI:10.13201/j.issn.1004-2806.2023.09.003
发表时间:2023
期刊:临床血液学杂志
影响因子:--
作者:杨漾;张义成
通讯作者:张义成
DOI:10.11768/nkjwzzzz20230203
发表时间:2023
期刊:内科急危重症杂志
影响因子:--
作者:杨漾;张义成
通讯作者:张义成
靶向mTORC2对MLL急性髓系白血病恶性造血维持的影响及分子机制研究
- 批准号:81500137
- 项目类别:青年科学基金项目
- 资助金额:18.0万元
- 批准年份:2015
- 负责人:杨漾
- 依托单位:
国内基金
海外基金
