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A FOXO1-induced oncogenic network defines the AML1-ETO pre-leukemic program

Shan Lin, Anetta Ptasinska, Xiaoting Chen, Mahesh Shrestha, Salam A. Assi, Paulynn S. Chin, Maria R. Imperato, Bruce Aronow, Jingsong Zhang, Matthew T. Weirauch, Constanze Bonifer and James C. Mulloy

Key points

  • Increased FOXO1 is oncogenic in human CD34+ cells and promotes pre-leukemia transition.

  • FOXO1 is required by AML1-ETO pre-leukemia cells for the activation of a stem cell molecular program.

Abstract

Understanding and blocking the self-renewal pathway of pre-leukemia 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 pre-leukemic cells expressing the t(8;21)-associated oncogene AML1-ETO (AE). Though generally considered as a tumor suppressor, FOXO1 is consistently upregulated in t(8;21) AML. Expression of FOXO1 in human CD34+ cells promotes a pre-leukemic 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 which is also present in AE pre-leukemia 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 as well as t(8;21) AML cell lines. Targeting of FOXO1 therefore provides a potential therapeutic strategy for elimination of stem cells at both pre-leukemic and leukemic stages.

  • Submitted November 10, 2016.
  • Accepted July 7, 2017.