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Blood. 2017 Sep 7;130(10):1213-1222. doi: 10.1182/blood-2016-11-750976. Epub 2017 Jul 14.

A FOXO1-induced oncogenic network defines the AML1-ETO preleukemic program.

Author information

1
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
2
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham, United Kingdom.
3
Center for Autoimmune Genomics and Etiology and.
4
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.
5
Department of Pharmacology and Physiology, St. Louis University School of Medicine, St. Louis, MO.

Abstract

Understanding and blocking the self-renewal pathway of preleukemia stem cells could prevent acute myeloid leukemia (AML) relapse. In this study, we show that increased FOXO1 represents a critical mechanism driving aberrant self-renewal in preleukemic cells expressing the t(8;21)-associated oncogene AML1-ETO (AE). Although generally considered as a tumor suppressor, FOXO1 is consistently upregulated in t(8;21) AML. Expression of FOXO1 in human CD34+ cells promotes a preleukemic state with enhanced self-renewal and dysregulated differentiation. The DNA binding domain of FOXO1 is essential for these functions. FOXO1 activates a stem cell molecular signature that is also present in AE preleukemia cells and preserved in t(8;21) patient samples. Genome-wide binding studies show that AE and FOXO1 share the majority of their binding sites, whereby FOXO1 binds to multiple crucial self-renewal genes and is required for their activation. In agreement with this observation, genetic and pharmacological ablation of FOXO1 inhibited the long-term proliferation and clonogenicity of AE cells and t(8;21) AML cell lines. Targeting of FOXO1 therefore provides a potential therapeutic strategy for elimination of stem cells at both preleukemic and leukemic stages.

PMID:
28710059
PMCID:
PMC5606002
DOI:
10.1182/blood-2016-11-750976
[Indexed for MEDLINE]
Free PMC Article

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