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.
Highlights
Acute myeloid leukaemia (AML) is a heterogeneous group of severe haematological diseases characterized by a block in myeloid differentiation and the unrestrained proliferation of immature myeloid cells (Estey & Dohner, 2006)
Generation of a blood cell‐specific conditional AE mouse model We initiated this study with the aim to analyse global signalling pathways and cellular mechanisms that operate during the progressive disease evolution downstream of the t(8;21) translocation
To be able to address the role of AE during the dynamic evolution towards manifest leukaemia and to dissect the molecular and cellular programs operating during this process, we wanted to establish a model that allows to conditionally and reversibly express AE in a fraction of all blood cell types
Summary
Acute myeloid leukaemia (AML) is a heterogeneous group of severe haematological diseases characterized by a block in myeloid differentiation and the unrestrained proliferation of immature myeloid cells (Estey & Dohner, 2006). Important insights into the molecular consequences of aberrant AE expression have been gained from microarray and chromatin immunoprecipitation experiments In these studies, transcriptional AE target genes and epigenetic modifications were identified that link AE function to cellular proliferation, self‐renewal and differentiation (Alcalay et al, 2003; Balgobind et al, 2011; Kvinlaug et al, 2011; Ptasinska et al, 2012; Ross et al, 2004; Valk et al, 2004). Transcriptional AE target genes and epigenetic modifications were identified that link AE function to cellular proliferation, self‐renewal and differentiation (Alcalay et al, 2003; Balgobind et al, 2011; Kvinlaug et al, 2011; Ptasinska et al, 2012; Ross et al, 2004; Valk et al, 2004) Because these experiments were based on the analysis of direct transcriptional modifications promoted by short‐term AE expression or deletion and on biopsies from AML patients, the stepwise evolution of transcriptome‐wide alterations downstream of the initial t(8;21) translocation are essentially unknown. In order to understand the cellular programs operating during the trajectory to leukaemia and to define novel therapeutic agents that can interfere with these pathways, it is critical to analyse preclinical mouse models that recapitulate the stepwise evolution and the initial mosaic expression of AE in blood cells characteristic of the human disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
