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Evolution of human BCR–ABL1 lymphoblastic leukaemia-initiating cells

Author

Listed:
  • Faiyaz Notta

    (Campbell Family Institute for Cancer Research/Ontario Cancer Institute
    University of Toronto)

  • Charles G. Mullighan

    (St Jude Children’s Research Hospital)

  • Jean C. Y. Wang

    (Campbell Family Institute for Cancer Research/Ontario Cancer Institute
    Princess Margaret Hospital, University of Toronto)

  • Armando Poeppl

    (Campbell Family Institute for Cancer Research/Ontario Cancer Institute)

  • Sergei Doulatov

    (Campbell Family Institute for Cancer Research/Ontario Cancer Institute
    University of Toronto)

  • Letha A. Phillips

    (St Jude Children’s Research Hospital)

  • Jing Ma

    (Hartwell Center for Bioinformatics and Biotechnology, St Jude Children’s Research Hospital)

  • Mark D. Minden

    (Princess Margaret Hospital, University of Toronto)

  • James R. Downing

    (St Jude Children’s Research Hospital)

  • John E. Dick

    (Campbell Family Institute for Cancer Research/Ontario Cancer Institute
    University of Toronto)

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.

Suggested Citation

  • Faiyaz Notta & Charles G. Mullighan & Jean C. Y. Wang & Armando Poeppl & Sergei Doulatov & Letha A. Phillips & Jing Ma & Mark D. Minden & James R. Downing & John E. Dick, 2011. "Evolution of human BCR–ABL1 lymphoblastic leukaemia-initiating cells," Nature, Nature, vol. 469(7330), pages 362-367, January.
    • Handle: RePEc:nat:nature:v:469:y:2011:i:7330:d:10.1038_nature09733
    DOI: 10.1038/nature09733
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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.

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