Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia |
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| Authors: | Hong Dengli Gupta Rajeev Ancliff Philip Atzberger Ann Brown John Soneji Shamit Green Joanne Colman Sue Piacibello Wanda Buckle Veronica Tsuzuki Shinobu Greaves Mel Enver Tariq |
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| Institution: | Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK. |
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| Abstract: | Understanding cancer pathogenesis requires knowledge of not only the specific contributory genetic mutations but also the cellular framework in which they arise and function. Here we explore the clonal evolution of a form of childhood precursor-B cell acute lymphoblastic leukemia that is characterized by a chromosomal translocation generating a TEL-AML1 fusion gene. We identify a cell compartment in leukemic children that can propagate leukemia when transplanted in mice. By studying a monochorionic twin pair, one preleukemic and one with frank leukemia, we establish the lineal relationship between these "cancer-propagating" cells and the preleukemic cell in which the TEL-AML1 fusion first arises or has functional impact. Analysis of TEL-AML1-transduced cord blood cells suggests that TEL-AML1 functions as a first-hit mutation by endowing this preleukemic cell with altered self-renewal and survival properties. |
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