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EMBO Mol Med. 2013 Dec;5(12):1804-20. doi: 10.1002/emmm.201302661. Epub 2013 Oct 4.

Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model.

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1
Medical Center of the Johannes Gutenberg-University Mainz, Department of Internal Medicine III, Division of Translational and Experimental Oncology, Mainz, Germany; German Cancer Research Center, Department of Stem Cells and Cancer, Heidelberg, Germany; Medical Center of the Johannes Gutenberg-University Mainz, Institute for Toxicology, Mainz, Germany.

Abstract

The t(8;21) chromosomal translocation activates aberrant expression of the AML1-ETO (AE) fusion protein and is commonly associated with core binding factor acute myeloid leukaemia (CBF AML). Combining a conditional mouse model that closely resembles the slow evolution and the mosaic AE expression pattern of human t(8;21) CBF AML with global transcriptome sequencing, we find that disease progression was characterized by two principal pathogenic mechanisms. Initially, AE expression modified the lineage potential of haematopoietic stem cells (HSCs), resulting in the selective expansion of the myeloid compartment at the expense of normal erythro- and lymphopoiesis. This lineage skewing was followed by a second substantial rewiring of transcriptional networks occurring in the trajectory to manifest leukaemia. We also find that both HSC and lineage-restricted granulocyte macrophage progenitors (GMPs) acquired leukaemic stem cell (LSC) potential being capable of initiating and maintaining the disease. Finally, our data demonstrate that long-term expression of AE induces an indolent myeloproliferative disease (MPD)-like myeloid leukaemia phenotype with complete penetrance and that acute inactivation of AE function is a potential novel therapeutic option.

KEYWORDS:

cancer stem cells; core binding factor acute myeloid leukaemia; preclinical mouse model; therapy target validation; whole transcriptome sequencing

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PMID:
24124051
PMCID:
PMC3914523
DOI:
10.1002/emmm.201302661
[Indexed for MEDLINE]
Free PMC Article
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