Article | Published:

Evolution of human BCR–ABL1 lymphoblastic leukaemia-initiating cells

Nature volume 469, pages 362367 (20 January 2011) | Download Citation

  • A Corrigendum to this article was published on 09 March 2011

This article has been updated

Abstract

Many tumours are composed of genetically diverse cells; however, little is known about how diversity evolves or the impact that diversity has on functional properties. Here, using xenografting and DNA copy number alteration (CNA) profiling of human BCR–ABL1 lymphoblastic leukaemia, we demonstrate that genetic diversity occurs in functionally defined leukaemia-initiating cells and that many diagnostic patient samples contain multiple genetically distinct leukaemia-initiating cell subclones. Reconstructing the subclonal genetic ancestry of several samples by CNA profiling demonstrated a branching multi-clonal evolution model of leukaemogenesis, rather than linear succession. For some patient samples, the predominant diagnostic clone repopulated xenografts, whereas in others it was outcompeted by minor subclones. Reconstitution with the predominant diagnosis clone was associated with more aggressive growth properties in xenografts, deletion of CDKN2A and CDKN2B, and a trend towards poorer patient outcome. Our findings link clonal diversity with leukaemia-initiating-cell function and underscore the importance of developing therapies that eradicate all intratumoral subclones.

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Change history

  • 10 March 2011

    Under the heading ‘Genetic basis of functional heterogeneity’, three citations to Fig. 2 were changed to Fig. 1 on 10 March 2011. Please see the corrigendum at the end of the PDF for details.

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Acknowledgements

We would like to thank S. Minkin for statistical analysis of patient outcome, the Dick Laboratory and B. Neel for critical review of this manuscript, M. Cooper for editorial assistance, and P. A. Penttilä, L. Jamieson, J. Yuan and S. Zhao for preparative flow cytometry. This work was supported by funds from Canadian Institutes for Health Research (CIHR) studentships (F.N., S.D.), the Pew Charitable Trusts (C.G.M.), The Stem Cell Network of Canadian National Centres of Excellence, the Canadian Cancer Society and the Terry Fox Foundation, Genome Canada through the Ontario Genomics Institute, Ontario Institute for Cancer Research with funds from the province of Ontario, the Leukemia and Lymphoma Society, the Canadian Institutes for Health Research, a Canada Research Chair, and the American and Lebanese Syrian Associated Charities of St Jude Children’s Research Hospital. This research was funded in part by the Ontario Ministry of Health and Long Term Care (OMOHLTC). The views expressed do not necessarily reflect those of the OMOHLTC.

Author information

Author notes

    • Faiyaz Notta
    •  & Charles G. Mullighan

    These authors contributed equally to this work.

Affiliations

  1. Division of Stem Cell and Developmental Biology, Campbell Family Institute for Cancer Research/Ontario Cancer Institute, Toronto, Ontario M5G 1L7, Canada

    • Faiyaz Notta
    • , Jean C. Y. Wang
    • , Armando Poeppl
    • , Sergei Doulatov
    •  & John E. Dick
  2. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1L7, Canada

    • Faiyaz Notta
    • , Sergei Doulatov
    •  & John E. Dick
  3. Department of Pathology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Charles G. Mullighan
    • , Letha A. Phillips
    •  & James R. Downing
  4. Department of Medical Oncology and Hematology, Princess Margaret Hospital, and Department of Medicine, University of Toronto, Toronto, Ontario M5G 2M9, Canada

    • Jean C. Y. Wang
    •  & Mark D. Minden
  5. Hartwell Center for Bioinformatics and Biotechnology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Jing Ma

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Contributions

F.N. designed study, analysed data and prepared figures. F.N., C.G.M., J.C.Y.W., A.P., S.D. and L.A.P. performed experiments. M.D.M. provided patient samples. J.C.Y.W. and M.D.M. provided patient outcome data. J.M. performed paired and unpaired segmentation analysis of SNP array data. F.N. and C.G.M analysed and interpreted SNP data. C.G.M., J.C.Y.W., S.D. and J.R.D. critically reviewed and edited the manuscript. F.N. and J.E.D. wrote the manuscript. J.E.D. supervised the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to John E. Dick.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Methods, a Supplementary Note, additional references and Supplementary Figures 1-18 with legends.

  2. 2.

    Supplementary Tables

    This file contains Supplementary Tables 1-7.

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DOI

https://doi.org/10.1038/nature09733

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