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

Yue Sheng,Jonathan D Licht,Xinyan Lu,Chunjie Yu,Yong Huang,Benjamin Mizukawa,Jianjun Chen,Yin Liu,Rui Ma,Zhijian Qian,Peng Ji,Chao Hu

doi:10.1038/s41467-020-14590-9

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.

Highlights

FOXM1, a known transcription factor, promotes cell proliferation in a variety of cancer cells
By using both mouse model and patient-derived xenograft (PDX) model, we provide a proof of concept that targeting Foxm[1] is a potential leukemia stem cells (LSCs)-directed treatment for Mixed lineage leukemia-rearranged (MLL-r) Acute myeloid leukemia (AML)
FOXM1 upregulation is associated with MLL-r AMLs

Summary

Introduction

FOXM1, a known transcription factor, promotes cell proliferation in a variety of cancer cells. We show that Foxm[1] is required for survival, quiescence and self-renewal of MLL-AF9 (MA9)-transformed leukemia stem cells (LSCs) in vivo. Relapse after initial achievement of complete remission remains a major challenge in AML treatment[1] Dick and his colleagues showed that AML is organized in a hierarchical fashion, being sustained by leukemia stem cell (LSCs) in vivo[2,3]. Our data reveal that survival of LSCs but not normal HSCs is sensitive to FOXM1 inhibition in both mouse and human By using both mouse model and patient-derived xenograft (PDX) model, we provide a proof of concept that targeting Foxm[1] is a potential LSC-directed treatment for MLL-r AML

Methods

Results

Conclusion