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Genetic variegation of clonal architecture and propagating cells in leukaemia

Author

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  • 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
    Present address: University College London Cancer Institute, London WC1E 6BT, UK.)

  • Mel Greaves

    (Section of Haemato-Oncology, The Institute of Cancer Research, Sutton SM2 5NG, UK)

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.

Suggested Citation

  • 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 & , 2011. "Genetic variegation of clonal architecture and propagating cells in leukaemia," Nature, Nature, vol. 469(7330), pages 356-361, January.
  • Handle: RePEc:nat:nature:v:469:y:2011:i:7330:d:10.1038_nature09650
    DOI: 10.1038/nature09650
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    Cited by:

    1. Naomi Kawashima & Yuichi Ishikawa & Jeong Hui Kim & Yoko Ushijima & Akimi Akashi & Yohei Yamaguchi & Hikaru Hattori & Marie Nakashima & Seara Ikeno & Rika Kihara & Takahiro Nishiyama & Takanobu Morish, 2022. "Comparison of clonal architecture between primary and immunodeficient mouse-engrafted acute myeloid leukemia cells," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Udit Singhal & Srinivas Nallandhighal & Jeffrey J. Tosoian & Kevin Hu & Trinh M. Pham & Judith Stangl-Kremser & Chia-Jen Liu & Razeen Karim & Komal R. Plouffe & Todd M. Morgan & Marcin Cieslik & Rober, 2024. "Integrative multi-region molecular profiling of primary prostate cancer in men with synchronous lymph node metastasis," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    3. Yi-Ing Chen & Chin-Chun Chang & Min-Fen Hsu & Yung-Ming Jeng & Yu-Wen Tien & Ming-Chu Chang & Yu-Ting Chang & Chun-Mei Hu & Wen-Hwa Lee, 2022. "Homophilic ATP1A1 binding induces activin A secretion to promote EMT of tumor cells and myofibroblast activation," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    4. Ayşegül Erdem & Silvia Marin & Diego A. Pereira-Martins & Roldán Cortés & Alan Cunningham & Maurien G. Pruis & Bauke Boer & Fiona A. J. Heuvel & Marjan Geugien & Albertus T. J. Wierenga & Annet Z. Bro, 2022. "The Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Yuxuan Liu & Zhimin Gu & Hui Cao & Pranita Kaphle & Junhua Lyu & Yuannyu Zhang & Wenhuo Hu & Stephen S. Chung & Kathryn E. Dickerson & Jian Xu, 2021. "Convergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    6. Hao Wang & R. Alejandro Sica & Gurbakhash Kaur & Phillip M. Galbo & Zhixin Jing & Christopher D. Nishimura & Xiaoxin Ren & Ankit Tanwar & Bijan Etemad-Gilbertson & Britta Will & Deyou Zheng & David Fo, 2024. "TMIGD2 is an orchestrator and therapeutic target on human acute myeloid leukemia stem cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Wenxue Ma & Alejandro Gutierrez & Daniel J Goff & Ifat Geron & Anil Sadarangani & Christina A M Jamieson & Angela C Court & Alice Y Shih & Qingfei Jiang & Christina C Wu & Kang Li & Kristen M Smith & , 2012. "NOTCH1 Signaling Promotes Human T-Cell Acute Lymphoblastic Leukemia Initiating Cell Regeneration in Supportive Niches," PLOS ONE, Public Library of Science, vol. 7(6), pages 1-14, June.

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