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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Research Support, N.I.H., Extramural

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

Substances

  • AML1-ETO fusion protein, human
  • Antigens, CD34
  • Core Binding Factor Alpha 2 Subunit
  • Forkhead Box Protein O1
  • Oncogene Proteins, Fusion
  • RUNX1 Translocation Partner 1 Protein