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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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