title: Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model.
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.
authors.affiliation: 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.
authors.forename: Nina
authors.initials: N
authors.lastname: Cabezas-Wallscheid
authors.forename: Victoria
authors.initials: V
authors.lastname: Eichwald
authors.forename: Jos
authors.initials: J
authors.lastname: de Graaf
authors.forename: Martin
authors.initials: M
authors.lastname: Löwer
authors.forename: Hans-Anton
authors.initials: HA
authors.lastname: Lehr
authors.forename: Andreas
authors.initials: A
authors.lastname: Kreft
authors.forename: Leonid
authors.initials: L
authors.lastname: Eshkind
authors.forename: Andreas
authors.initials: A
authors.lastname: Hildebrandt
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Abassi
authors.forename: Rosario
authors.initials: R
authors.lastname: Heck
authors.forename: Anna Katharina
authors.initials: AK
authors.lastname: Dehof
authors.forename: Svetlana
authors.initials: S
authors.lastname: Ohngemach
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.forename: Simone
authors.initials: S
authors.lastname: Wörtge
authors.forename: Steffen
authors.initials: S
authors.lastname: Schmitt
authors.forename: Johannes
authors.initials: J
authors.lastname: Lotz
authors.forename: Claudius
authors.initials: C
authors.lastname: Meyer
authors.forename: Thomas
authors.initials: T
authors.lastname: Kindler
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
authors.forename: John C
authors.initials: JC
authors.lastname: Castle
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bockamp
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D019070:Cell Lineage; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D055014:Granulocyte-Macrophage Progenitor Cells / Q000166:cytology / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010641:Phenotype; D017423:Sequence Analysis, RNA; D014178:Translocation, Genetic / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D015514:Oncogene Proteins, Fusion; D004317:Doxorubicin
keywords: cancer stem cells; core binding factor acute myeloid leukaemia; preclinical mouse model; therapy target validation; whole transcriptome sequencing