FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML.,Nature Communications

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FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML.
Nature Communications ( IF 14.7 ) Pub Date : 2020-02-17 , DOI: 10.1038/s41467-020-14590-9
Yue Sheng _{1,

2} , Chunjie Yu _{1,

2} , Yin Liu _{1,

2} , Chao Hu ₂ , Rui Ma ₃ , Xinyan Lu ₄ , Peng Ji ₄ , Jianjun Chen ₅ , Benjamin Mizukawa ₆ , Yong Huang ₇ , Jonathan D Licht ₁ , Zhijian Qian _{1,

2}

Affiliation

FOXM1, a known transcription factor, promotes cell proliferation in a variety of cancer cells. Here we show that Foxm1 is required for survival, quiescence and self-renewal of MLL-AF9 (MA9)-transformed leukemia stem cells (LSCs) in vivo. Mechanistically, Foxm1 upregulation activates the Wnt/β-catenin signaling pathways by directly binding to β-catenin and stabilizing β-catenin protein through inhibiting its degradation, thereby preserving LSC quiescence, and promoting LSC self-renewal in MLL-rearranged AML. More importantly, inhibition of FOXM1 markedly suppresses leukemogenic potential and induces apoptosis of primary LSCs from MLL-rearranged AML patients in vitro and in vivo in xenograft mice. Thus, our study shows a critical role and mechanisms of Foxm1 in MA9-LSCs, and indicates that FOXM1 is a potential therapeutic target for selectively eliminating LSCs in MLL-rearranged AML.

中文翻译：

FOXM1在MLL重排的AML中调节白血病干细胞的静止和存活。

FOXM1是一种已知的转录因子，可促进多种癌细胞中的细胞增殖。在这里，我们显示Foxm1是体内MLL-AF9（MA9）转化的白血病干细胞（LSCs）存活，静止和自我更新所必需的。从机制上讲，Foxm1的上调通过直接结合β-catenin并通过抑制其降解来稳定β-catenin蛋白，从而保持LSC静止并促进MLL重排AML中LSC的自我更新，从而直接激活β-catenin从而激活Wnt /β-catenin信号通路。更重要的是，在异种移植小鼠中，FOXM1的抑制作用显着抑制了致白血病的潜力，并诱导了来自MLL重排的AML患者的原代LSC的凋亡。因此，我们的研究表明Foxm1在MA9-LSC中的关键作用和机制，

更新日期：2020-02-17

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