Journal Article

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

Löwer, Martin, Kaina, Bernd, Kindler, Thomas, Sprengel, Rolf, Cabezas‐Wallscheid, Nina, Kreft, Andreas, Castle, John C., Schmitt, Steffen, Eichwald, Victoria, Wörtge, Simone, Dehof, Anna Katharina, Sahin, Ugur, Bockamp, Ernesto, Eshkind, Leonid, Hildebrandt, Andreas, Heck, Rosario, Trumpp, Andreas, de Graaf, Jos, Lehr, Hans‐Anton, Lotz, Johannes, Ohngemach, Svetlana, Meyer, Claudius, Zhang, Dong‐Er, Abassi, Yasmin

2013

Overview

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. Graphical Abstract This novel model system of AML1‐ETO driven acute myeloid leukaemia addresses the concept of ‘oncogene addiction’. Better understanding of AML1‐ETO need to maintain leukemia and rewire the transcriptome may help to design future therapies.

• Publisher: Nature Publishing Group UK,John Wiley and Sons,Springer Nature
• Subject: Animals / Antibiotics, Antineoplastic - pharmacology / Antibiotics, Antineoplastic - therapeutic use / cancer stem cells / Cell Lineage / core binding factor acute myeloid leukaemia / Disease Models, Animal / Doxorubicin - pharmacology / Doxorubicin - therapeutic use / Gene Expression Regulation - drug effects / Granulocyte-Macrophage Progenitor Cells - cytology / Granulocyte-Macrophage Progenitor Cells - metabolism / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - metabolism / Immunophenotyping / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - metabolism / Leukemia, Myeloid, Acute - pathology / Mice / Mice, Inbred C57BL / Neoplastic Stem Cells - cytology / Neoplastic Stem Cells - metabolism / Oncogene Proteins, Fusion - metabolism / Phenotype / preclinical mouse model / Research Article / Sequence Analysis, RNA / therapy target validation / Translocation, Genetic - drug effects / whole transcriptome sequencing