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

Research output: Contribution to journalArticle

Authors

  • Shan Lin
  • Xiaoting Chen
  • Mahesh Shrestha
  • B. J. Aronow
  • Jingsong Zhang
  • Matthew T. Weirauch
  • James C. Mulloy

Colleges, School and Institutes

External organisations

  • Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center
  • Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.
  • Department of Pharmacology and Physiology, St. Louis University School of Medicine

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.

Details

Original languageEnglish
Pages (from-to)1213-1222
Number of pages10
JournalBlood
Volume130
Issue number10
Early online date14 Jul 2017
Publication statusPublished - 7 Sep 2017

Keywords

  • Animals, Antigens, CD34, Cell Line, Tumor, Cell Proliferation, Core Binding Factor Alpha 2 Subunit, Forkhead Box Protein O1, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Gene Regulatory Networks, Genome, Human, Hematopoietic Stem Cells, Humans, Leukemia, Myeloid, Acute, Mice, SCID, Oncogene Proteins, Fusion, Precancerous Conditions, RUNX1 Translocation Partner 1 Protein, Up-Regulation, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Research Support, N.I.H., Extramural