E-MTAB-1820 - Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model
Released on 15 October 2013, last updated on 2 May 2014
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 (HSC), 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 (GMP) 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 (MPD)-like myeloid leukaemia phenotype with complete penetrance and that acute inactivation of AE function is a potential novel therapeutic option.
RNA-seq of coding RNA, co-expression, disease state design, in vivo, time series design
Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model. Cabezas-Wallscheid N, Eichwald V, de Graaf J, Löwer M, Lehr HA, Kreft A, Eshkind L, Hildebrandt A, Abassi Y, Heck R, Dehof AK, Ohngemach S, Sprengel R, Wörtge S, Schmitt S, Lotz J, Meyer C, Kindler T, Zhang DE, Kaina B, Castle JC, Trumpp A, Sahin U, Bockamp E. :1804-1820 (2013), Europe PMC 24124051
Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model. Nina Cabezas-Wallscheid, Victoria Eichwald, Jos de Graaf, Martin Lower, Hans-Anton Lehr, Andreas Kreft, Leonid Eshkind, Andreas Hildebrandt, Yasmin Abassi, Rosario Heck, Anna Katharina Dehof, Svetlana Ohngemach, Rolf Sprengel, Simone Wortge, Steffen Schmitt, Johannes Lotz, Claudius Meyer, Thomas Kindler, Dong-Er Zhang, Bernd Kaina, John C. Castle, Andreas Trumpp, Ugur Sahin and Ernesto Bockamp. EMBO Molecular Medicine (2013)