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Acute myeloid leukemia

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

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

Blood. 2017 Jul 14;:

Authors: Lin S, Ptasinska A, Chen X, Shrestha M, Assi SA, Chin PS, Imperato MR, Aronow B, Zhang J, Weirauch MT, Bonifer C, Mulloy JC

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.

PMID: 28710059 [PubMed - as supplied by publisher]

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