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

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          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.

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          Most cited references42

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          Prognostically useful gene-expression profiles in acute myeloid leukemia.

          In patients with acute myeloid leukemia (AML) a combination of methods must be used to classify the disease, make therapeutic decisions, and determine the prognosis. However, this combined approach provides correct therapeutic and prognostic information in only 50 percent of cases. We determined the gene-expression profiles in samples of peripheral blood or bone marrow from 285 patients with AML using Affymetrix U133A GeneChips containing approximately 13,000 unique genes or expression-signature tags. Data analyses were carried out with Omniviz, significance analysis of microarrays, and prediction analysis of microarrays software. Statistical analyses were performed to determine the prognostic significance of cases of AML with specific molecular signatures. Unsupervised cluster analyses identified 16 groups of patients with AML on the basis of molecular signatures. We identified the genes that defined these clusters and determined the minimal numbers of genes needed to identify prognostically important clusters with a high degree of accuracy. The clustering was driven by the presence of chromosomal lesions (e.g., t(8;21), t(15;17), and inv(16)), particular genetic mutations (CEBPA), and abnormal oncogene expression (EVI1). We identified several novel clusters, some consisting of specimens with normal karyotypes. A unique cluster with a distinctive gene-expression signature included cases of AML with a poor treatment outcome. Gene-expression profiling allows a comprehensive classification of AML that includes previously identified genetically defined subgroups and a novel cluster with an adverse prognosis. Copyright 2004 Massachusetts Medical Society
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            Acute myeloid leukaemia.

            Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haemopoietic progenitor cells and the most common malignant myeloid disorder in adults. The median age at presentation for patients with AML is 70 years. In the past few years, research in molecular biology has been instrumental in deciphering the pathogenesis of the disease. Genetic defects are thought to be the most important factors in determining the response to chemotherapy and outcome. Whereas significant progress has been made in the treatment of younger adults, the prospects for elderly patients have remained dismal, with median survival times of only a few months. This difference is related to comorbidities associated with ageing and to disease biology. Current efforts in clinical research focus on the assessment of targeted therapies. Such new approaches will probably lead to an increase in the cure rate.
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              Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region.

              Acute myelogenous leukemia (AML) is the most common adult leukemia, characterized by the clonal expansion of immature myeloblasts initiating from rare leukemic stem (LS) cells. To understand the functional properties of human LS cells, we developed a primary human AML xenotransplantation model using newborn nonobese diabetic/severe combined immunodeficient/interleukin (NOD/SCID/IL)2r gamma(null) mice carrying a complete null mutation of the cytokine gamma c upon the SCID background. Using this model, we demonstrated that LS cells exclusively recapitulate AML and retain self-renewal capacity in vivo. They home to and engraft within the osteoblast-rich area of the bone marrow, where AML cells are protected from chemotherapy-induced apoptosis. Quiescence of human LS cells may be a mechanism underlying resistance to cell cycle-dependent cytotoxic therapy. Global transcriptional profiling identified LS cell-specific transcripts that are stable through serial transplantation. These results indicate the potential utility of this AML xenograft model in the development of novel therapeutic strategies targeted at LS cells.
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                Author and article information

                Journal
                EMBO Mol Med
                EMBO Mol Med
                emmm
                EMBO Molecular Medicine
                John Wiley and Sons
                1757-4676
                1757-4684
                December 2013
                04 October 2013
                : 5
                : 12
                : 1804-1820
                Affiliations
                [1 ]Medical Center of the Johannes Gutenberg-University Mainz, Department of Internal Medicine III, Division of Translational and Experimental Oncology Mainz, Germany
                [2 ]German Cancer Research Center, Department of Stem Cells and Cancer Heidelberg, Germany
                [3 ]Medical Center of the Johannes Gutenberg-University Mainz, Institute for Toxicology Mainz, Germany
                [4 ]German Cancer Research Center, Division of Molecular Immunology Heidelberg, Germany
                [5 ]TRON – Translational Oncology at the Johannes Gutenberg-University Mainz Mainz, Germany
                [6 ]University of Lausanne, Institut Universitaire de Pathologie, CHUV Lausanne, Switzerland
                [7 ]Medical Center of the Johannes Gutenberg-University Mainz, Department of Pathology Mainz, Germany
                [8 ]Johannes Gutenberg-University Mainz, Institute for Informatics Mainz, Germany
                [9 ]Saarland University, Center for Bioinformatics Saarbrücken, Germany
                [10 ]Max-Planck-Institute for Medical Research Heidelberg, Germany
                [11 ]Medical Center of the Johannes Gutenberg-University Mainz, Institute for Molecular Medicine Mainz, Germany
                [12 ]German Cancer Research Center, FACS Core Facility Heidelberg, Germany
                [13 ]Medical Center of the Johannes Gutenberg-University Mainz, Institute of Clinical Chemistry and Laboratory Medicine Mainz, Germany
                [14 ]Medical Center of the Johannes Gutenberg-University Mainz Children's Hospital Mainz, Germany
                [15 ]Me, dical Center of the Johannes Gutenberg-University Mainz, Division of Haematology, Oncology and Pneumology, III. Medical Department Mainz, Germany
                [16 ]Department of Pathology, University of California San Diego, Division of Biological Sciences and Moores UCSD Cancer Center San Diego, CA, USA
                Author notes
                * Corresponding author: Tel: +49 6131 17 9784; Fax: +49 6131 230506;, E-mail: bockamp@ 123456uni-mainz.de
                Article
                10.1002/emmm.201302661
                3914523
                24124051
                42335802-a708-4f6e-a1d3-a74801f72cdc
                © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 February 2013
                : 28 August 2013
                : 28 August 2013
                Categories
                Research Articles

                Molecular medicine
                cancer stem cells,core binding factor acute myeloid leukaemia,preclinical mouse model,therapy target validation,whole transcriptome sequencing

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