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Nature. 2014 Feb 20;506(7488):328-33. doi: 10.1038/nature13038. Epub 2014 Feb 12.

Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.

Author information

1
1] Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada [2].
2
Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada.
3
1] Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada [2] Department of Medicine, University of Toronto, Toronto, Ontario M5S 2J7, Canada [3] Division of Medical Oncology and Hematology, UHN, Toronto, Ontario M5G 2M9, Canada.
4
1] Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada [2] Department of Medicine, University of Toronto, Toronto, Ontario M5S 2J7, Canada [3] Division of Medical Oncology and Hematology, UHN, Toronto, Ontario M5G 2M9, Canada [4] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
5
1] Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada [2] Radboud University, Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands.
6
Chonnam National University Hwasun Hospital, Genome Research Center for Hematopoietic Diseases, Gwangju 519-809, South Korea.
7
1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada [2] Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
8
1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada [2] Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada [3] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
9
Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
10
1] Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
11
1] Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

Erratum in

  • Nature. 2014 Apr 17;508(7496):420. Yousif, Fouad [added].

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 (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-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 DNMT3A(mut) 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.

PMID:
24522528
PMCID:
PMC4991939
DOI:
10.1038/nature13038
[Indexed for MEDLINE]
Free PMC Article
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