Rictor has a pivotal role in maintaining quiescence as well as stemness of leukemia stem cells in MLL-driven leukemia
Rictor has a pivotal role in maintaining quiescence as well as stemness of leukemia stem cells in MLL-driven leukemia
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在 MLL 驱动的白血病中，Rictor 在维持白血病干细胞的静止和干性方面发挥着关键作用。
DOI：
10.1038/leu.2016.223
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发表时间：
2017-02-01
期刊：
影响因子：
11.4
通讯作者：
Zhou, J.
中科院分区：
文献类型：
--
作者：
Fang, Y.;Yang, Y.;Zhou, J.
关于 Rictor/mTORC2 在急性髓性白血病的白血病发生中的作用知之甚少。在这里，我们证明 Rictor 通过防止白血病干细胞 (LSC) 耗竭，对于维持混合谱系白血病 (MLL) 驱动的白血病至关重要。 Rictor 耗竭通过促进 mTORC1 组装而导致 mTORC1 信号传导的反应性激活。过度激活的 mTORC1 信号转而驱动 LSC 进入循环，损害 LSC 的静止状态，并最终耗尽其产生白血病的能力。与此同时，Rictor 的缺失导致白血病细胞中 FoxO3a 的反应性激活，这作为负反馈抑制 mTORC1 活性的过度再激活，并矛盾地保护白血病细胞免于耗竭。同时消除 Rictor 和 FoxO3a 能够快速耗尽 MLL LSC，并快速根除 MLL 白血病。因此，我们目前的研究结果强调了 Rictor-FoxO3a 在维持 LSC 的静止和干性方面的关键调控轴。
Little is known about the roles of Rictor/mTORC2 in the leukemogenesis of acute myeloid leukemia. Here, we demonstrated that Rictor is essential for the maintenance of mixed lineage leukemia (MLL)-driven leukemia by preventing leukemia stem cells (LSCs) from exhaustion. 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. At the same time, 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. Simultaneous depletion of Rictor and FoxO3a enabled rapid exhaustion of MLL LSCs and a quick eradication of MLL leukemia. As such, our present findings highlighted a pivotal regulatory axis of Rictor-FoxO3a in maintaining quiescence and the stemness of LSCs.