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; Zhijian Qian

doi:10.1038/s41467-020-14590-9

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, Zhijian Qian^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

63 Scopus citations

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.

Original language	English (US)
Article number	928
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14590-9
State	Published - Dec 1 2020

Funding

This work was supported in part by National Institute of Health grant R01-HL131444, DK107615 and UF Institute funding to Z.Q., and Z.Q. is a Leukemia &Lymphoma Society (LLS) Scholar.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-020-14590-9

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title = "FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML",

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.",

author = "Yue Sheng and Chunjie Yu and Yin Liu and Chao Hu and Rui Ma and Xinyan Lu and Peng Ji and Jianjun Chen and Benjamin Mizukawa and Yong Huang and Licht, {Jonathan D.} and Zhijian Qian",

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doi = "10.1038/s41467-020-14590-9",

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AU - Sheng, Yue

AU - Yu, Chunjie

AU - Liu, Yin

AU - Hu, Chao

AU - Ma, Rui

AU - Lu, Xinyan

AU - Ji, Peng

AU - Chen, Jianjun

AU - Mizukawa, Benjamin

AU - Huang, Yong

AU - Licht, Jonathan D.

AU - Qian, Zhijian

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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