Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia

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, Monica Doedens, Jessie J. F. Medeiros, Rene Marke, Hyeoung Joon Kim, Kwon Lee, John D. McPherson, Thomas J. Hudson, The HALT Pan-Leukemia Gene Panel Consortium, Andrew M. K. Brown, Fouad Yousif, Quang M. Trinh, Lincoln D. Stein, Mark D. Minden, Jean C. Y. Wang and John E. Dick ()
Additional contact information
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
Vikas Gupta: Princess Margaret Cancer Centre, University Health Network (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
Andre C. Schuh: Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada
Karen W. Yee: Princess Margaret Cancer Centre, University Health Network (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
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
Thomas J. Hudson: University of Toronto, Toronto, Ontario M5G 2M9, 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
Mark D. Minden: Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada
Jean C. Y. Wang: Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada
John E. Dick: Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada

Nature, 2014, vol. 506, issue 7488, 328-333

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13038

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