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          Institute: MPI für medizinische Forschung     Collection: Jahbruch 2014_archival     Display Documents

ID: 681490.0, MPI für medizinische Forschung / Jahbruch 2014_archival
Instruction of haematopoietic lineage
choices, evolution of transcriptional
landscapes and cancer stem cell hierarchies
derived from an AML1‐ETO mouse model
Translation of Title:Instruction of haematopoietic lineage
choices, evolution of transcriptional
landscapes and cancer stem cell hierarchies
derived from an AML1‐ETO mouse model
Authors:Cabezas−Wallscheid, Nina; Eichwald, Victoria; de Graaf, Jos; Löwer, Martin; Lehr, Hans−Anton; Kreft, Andreas; Eshkind, Leonid; Hildebrandt, Andreas; Abassi, Yasmin; Heck, Rosario; Dehof, Anna Katharina; Ohngemach, Svetlana; Sprengel, Rolf; Wörtge, Simone; Schmitt, Steffen; Lotz, Johannes; Meyer, Claudius; Kindler, Thomas; Zhang, Dong−Er; Kaina, Bernd; Castle, John C.; Trumpp, Andreas; Sahin, Ugur; Bockamp, Ernesto
Date of Publication (YYYY-MM-DD):2013-12-01
Title of Journal:EMBO Molecular Medicine
Journal Abbrev.:EMBO molecular medicine
Issue / Number:12
Start Page:1804
End Page:1820
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description: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
Free Keywords:cancer stem cells, core binding factor acute myeloid leukaemia, preclinical mouse model, therapy target validation, whole transcriptome sequencing
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:wkaiser
Affiliations:MPI für medizinische Forschung/Abteilung Molekulare Neurobiologie
MPI für medizinische Forschung/Abteilung Zellphysiologie/Olfaction Web
MPI für medizinische Forschung/Abteilung Molekulare Neurobiologie/Gruppe Rolf Sprengel
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