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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Serval ID
serval:BIB_281C8690BBDD
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model.
Journal
Embo Molecular Medicine
Author(s)
Cabezas-Wallscheid N., Eichwald V., de Graaf J., Löwer M., Lehr H.A., Kreft A., Eshkind L., Hildebrandt A., Abassi Y., Heck R., Dehof A.K., Ohngemach S., Sprengel R., Wörtge S., Schmitt S., Lotz J., Meyer C., Kindler T., Zhang D.E., Kaina B., Castle J.C., Trumpp A., Sahin U., Bockamp E.
ISSN
1757-4684 (Electronic)
ISSN-L
1757-4676
Publication state
Published
Issued date
2013
Volume
5
Number
12
Pages
1804-1820
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
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
Pubmed
Web of science
Open Access
Yes
Create date
11/11/2013 16:18
Last modification date
20/08/2019 13:07
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