Genetic variegation of clonal architecture and propagating cells in leukaemia

Kristina Anderson, Christoph Lutz, Frederik W. van Delft, Caroline M. Bateman, Yanping Guo, Susan M. Colman, Helena Kempski, Anthony V. Moorman, Ian Titley, John Swansbury, Lyndal Kearney, Tariq Enver and Mel Greaves ()
Additional contact information
Kristina Anderson: Section of Haemato-Oncology, The Institute of Cancer Research, Sutton SM2 5NG, UK
Christoph Lutz: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK
Frederik W. van Delft: Section of Haemato-Oncology, The Institute of Cancer Research, Sutton SM2 5NG, UK
Caroline M. Bateman: Section of Haemato-Oncology, The Institute of Cancer Research, Sutton SM2 5NG, UK
Yanping Guo: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK
Susan M. Colman: Section of Haemato-Oncology, The Institute of Cancer Research, Sutton SM2 5NG, UK
Helena Kempski: Paediatric Malignancy Unit, Great Ormond Street Hospital & UCL Institute of Child Health, London WC1N 3JH, UK
Anthony V. Moorman: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK
Ian Titley: Section of Haemato-Oncology, The Institute of Cancer Research, Sutton SM2 5NG, UK
John Swansbury: Section of Haemato-Oncology, The Institute of Cancer Research, Sutton SM2 5NG, UK
Lyndal Kearney: Section of Haemato-Oncology, The Institute of Cancer Research, Sutton SM2 5NG, UK
Tariq Enver: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK
Mel Greaves: Section of Haemato-Oncology, The Institute of Cancer Research, Sutton SM2 5NG, UK

Nature, 2011, vol. 469, issue 7330, 356-361

Abstract: Abstract Little is known of the genetic architecture of cancer at the subclonal and single-cell level or in the cells responsible for cancer clone maintenance and propagation. Here we have examined this issue in childhood acute lymphoblastic leukaemia in which the ETV6–RUNX1 gene fusion is an early or initiating genetic lesion followed by a modest number of recurrent or ‘driver’ copy number alterations. By multiplexing fluorescence in situ hybridization probes for these mutations, up to eight genetic abnormalities can be detected in single cells, a genetic signature of subclones identified and a composite picture of subclonal architecture and putative ancestral trees assembled. Subclones in acute lymphoblastic leukaemia have variegated genetics and complex, nonlinear or branching evolutionary histories. Copy number alterations are independently and reiteratively acquired in subclones of individual patients, and in no preferential order. Clonal architecture is dynamic and is subject to change in the lead-up to a diagnosis and in relapse. Leukaemia propagating cells, assayed by serial transplantation in NOD/SCID IL2Rγnull mice, are also genetically variegated, mirroring subclonal patterns, and vary in competitive regenerative capacity in vivo. These data have implications for cancer genomics and for the targeted therapy of cancer.

Date: 2011
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DOI: 10.1038/nature09650

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