Journal
NATURE
Volume 506, Issue 7488, Pages 328-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13038
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Funding
- McEwen Centre for Regenerative Medicine
- Gentle Ben Charity
- Canadian Institutes for Health Research (CIHR)
- Aplastic Anemia and Myelodysplasia Association of Canada
- Vetenskapsradet
- CIHR
- Canadian Cancer Society
- Terry Fox Foundation
- Genome Canada through the Ontario Genomics Institute
- Ontario Institute for Cancer Research
- province of Ontario
- Canada Research Chair
- Ontario Ministry of Health and Long Term Care (OMOHLTC)
- Cancer Stem Cell Consortium
- Government of Canada through Genome Canada
- Government of Canada through Ontario Genomics Institute [OGI-047]
- Government of Canada through Canadian Institutes of Health Research [CSC-105367]
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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.
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