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Publication Detail

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

Authors: Lin, Shan; Ptasinska, Anetta; Chen, Xiaoting; Shrestha, Mahesh; Assi, Salam A; Chin, Paulynn S; Imperato, Maria R; Aronow, B J; Zhang, Jingsong; Weirauch, Matthew T; Bonifer, Constanze; Mulloy, James C

Published In Blood, (2017 09 07)

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.

PubMed ID: 28710059 Exiting the NIEHS site

MeSH Terms: Animals; Antigens, CD34/metabolism; Cell Line, Tumor; Cell Proliferation; Core Binding Factor Alpha 2 Subunit/genetics; Core Binding Factor Alpha 2 Subunit/metabolism*; Forkhead Box Protein O1/metabolism*; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Gene Regulatory Networks*; Genome, Human; Hematopoietic Stem Cells/metabolism; Humans; Leukemia, Myeloid, Acute/genetics*; Leukemia, Myeloid, Acute/pathology; Mice, SCID; Oncogene Proteins, Fusion/genetics; Oncogene Proteins, Fusion/metabolism*; Precancerous Conditions/genetics*; Precancerous Conditions/pathology; RUNX1 Translocation Partner 1 Protein; Up-Regulation/genetics

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