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Science 18 January 2008:
Vol. 319. no. 5861, pp. 336 - 339
DOI: 10.1126/science.1150648
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Reports

Initiating and Cancer-Propagating Cells in TEL-AML1-Associated Childhood Leukemia

Dengli Hong,1 Rajeev Gupta,1 Philip Ancliff,2 Ann Atzberger,1 John Brown,1 Shamit Soneji,1 Joanne Green,1 Sue Colman,5 Wanda Piacibello,4 Veronica Buckle,1 Shinobu Tsuzuki,3 Mel Greaves,5 Tariq Enver1*

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.

1 Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
2 Department of Haematology, Great Ormond Street Hospital, and Department of Molecular Haematology and Cancer Biology, Institute of Child Health, University College London, WC1N 3JH, UK.
3 Division of Molecular Medicine, Aichi Cancer Research Institute, Nagoya 464-8681, Japan.
4 Division of Research in Medical Oncology, Institute for Cancer Research and Treatment, Strada Provinciale 142, 10060 Candiolo, Torino, Italy.
5 Section of Haemato-Oncology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.

* To whom correspondence should be addressed. E-mail: tenver{at}gwmail.jr2.ox.ac.uk

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Science. ISSN 0036-8075 (print), 1095-9203 (online)