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Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia

Author

Listed:
  • Liran I. Shlush

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada)

  • Sasan Zandi

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada)

  • Amanda Mitchell

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada)

  • Weihsu Claire Chen

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada)

  • Joseph M. Brandwein

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada
    University of Toronto, Toronto, Ontario M5S 2J7, Canada
    UHN, Toronto, Ontario M5G 2M9, Canada)

  • Vikas Gupta

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada
    University of Toronto, Toronto, Ontario M5S 2J7, Canada
    UHN, Toronto, Ontario M5G 2M9, Canada)

  • James A. Kennedy

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada)

  • Aaron D. Schimmer

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada
    University of Toronto, Toronto, Ontario M5S 2J7, Canada
    UHN, Toronto, Ontario M5G 2M9, Canada
    University of Toronto, Toronto, Ontario M5G 2M9, Canada)

  • Andre C. Schuh

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada
    University of Toronto, Toronto, Ontario M5S 2J7, Canada
    UHN, Toronto, Ontario M5G 2M9, Canada)

  • Karen W. Yee

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada
    University of Toronto, Toronto, Ontario M5S 2J7, Canada
    UHN, Toronto, Ontario M5G 2M9, Canada)

  • Jessica L. McLeod

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada)

  • Monica Doedens

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada)

  • Jessie J. F. Medeiros

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada)

  • Rene Marke

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada
    Radboud University, Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands)

  • Hyeoung Joon Kim

    (Chonnam National University Hwasun Hospital, Genome Research Center for Hematopoietic Diseases, Gwangju 519-809, South Korea)

  • Kwon Lee

    (Chonnam National University Hwasun Hospital, Genome Research Center for Hematopoietic Diseases, Gwangju 519-809, South Korea)

  • John D. McPherson

    (University of Toronto, Toronto, Ontario M5G 2M9, Canada
    Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada)

  • Thomas J. Hudson

    (University of Toronto, Toronto, Ontario M5G 2M9, Canada
    Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada
    University of Toronto, Toronto, Ontario M5S 1A8, Canada)

  • The HALT Pan-Leukemia Gene Panel Consortium

    (†Lists of participants and their affiliations appear in Supplementary Information.)

  • Andrew M. K. Brown

    (Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada)

  • Fouad Yousif

    (Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada)

  • Quang M. Trinh

    (Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada)

  • Lincoln D. Stein

    (Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada
    University of Toronto, Toronto, Ontario M5S 1A8, Canada)

  • Mark D. Minden

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada
    University of Toronto, Toronto, Ontario M5S 2J7, Canada
    UHN, Toronto, Ontario M5G 2M9, Canada
    University of Toronto, Toronto, Ontario M5G 2M9, Canada)

  • Jean C. Y. Wang

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada
    University of Toronto, Toronto, Ontario M5S 2J7, Canada
    UHN, Toronto, Ontario M5G 2M9, Canada)

  • John E. Dick

    (Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada
    University of Toronto, Toronto, Ontario M5S 1A8, Canada)

Abstract

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3Amut) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3Amut-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3Amut arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.

Suggested Citation

  • Liran I. Shlush & Sasan Zandi & Amanda Mitchell & Weihsu Claire Chen & Joseph M. Brandwein & Vikas Gupta & James A. Kennedy & Aaron D. Schimmer & Andre C. Schuh & Karen W. Yee & Jessica L. McLeod & Mo, 2014. "Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia," Nature, Nature, vol. 506(7488), pages 328-333, February.
    • Handle: RePEc:nat:nature:v:506:y:2014:i:7488:d:10.1038_nature13038
    DOI: 10.1038/nature13038
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