FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML

Yue Sheng, Chunjie Yu, Yin Liu, Chao Hu, Rui Ma, Xinyan Lu, Peng Ji, Jianjun Chen, Benjamin Mizukawa, Yong Huang, Jonathan D. Licht and Zhijian Qian ()
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Yue Sheng: University of Florida
Chunjie Yu: University of Florida
Yin Liu: University of Florida
Chao Hu: University of Illinois at Chicago
Rui Ma: University of Illinois at Chicago
Xinyan Lu: Feinberg School of Medicine
Peng Ji: Feinberg School of Medicine
Jianjun Chen: Department of System Biology
Benjamin Mizukawa: Cancer & Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center
Yong Huang: University of Virginia
Jonathan D. Licht: University of Florida
Zhijian Qian: University of Florida

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-14590-9

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