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RESEARCH PRODUCT
Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model.
Rolf SprengelRosario HeckYasmin AbassiAndreas KreftJos De GraafAnna Katharina DehofNina Cabezas-wallscheidAndreas HildebrandtSteffen SchmittSvetlana OhngemachUgur SahinHans A. LehrJohannes LotzDong-er ZhangSimone WörtgeSimone WörtgeJohn C. CastleThomas KindlerVictoria EichwaldAndreas TrumppErnesto BockampMartin LöwerClaudius U. MeyerBernd KainaLeonid Eshkindsubject
cancer stem cellsCancer stem cells; Core binding factor acute myeloid leukaemia; Preclinical mouse model; Therapy target validation; Whole transcriptome sequencingMyeloidtherapy target validationOncogene Proteins FusionCloseupsBiologyGranulocyte-Macrophage Progenitor CellsTranslocation Geneticwhole transcriptome sequencingImmunophenotypingMiceGranulocyte-Macrophage Progenitor CellsCancer stem cellhemic and lymphatic diseasesmedicineAML1-ETOAnimalsCell Lineageacute myeloid leukaemiaLymphopoiesisProgenitor cellt(8;21)Research Articlespreclinical mouse modelGeneticsRegulation of gene expressionAntibiotics AntineoplasticSequence Analysis RNAcore binding factor acute myeloid leukaemiainducible mouse-modelHematopoietic Stem CellsMice Inbred C57BLDisease Models AnimalLeukemia Myeloid AcuteHaematopoiesisPhenotypemedicine.anatomical_structureGene Expression RegulationDoxorubicinCancer researchNeoplastic Stem CellsMolecular MedicineStem celldescription
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.
year | journal | country | edition | language |
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2013-10-01 |