title: Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.
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.
authors: 1] Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada [2].
authors: Liran I
authors: LI
authors: Shlush
authors: 1] Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada [2].
authors: Sasan
authors: S
authors: Zandi
authors: Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada.
authors: Amanda
authors: A
authors: Mitchell
authors: Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada.
authors: Weihsu Claire
authors: WC
authors: Chen
authors: 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.
authors: Joseph M
authors: JM
authors: Brandwein
authors: 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.
authors: Vikas
authors: V
authors: Gupta
authors: Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada.
authors: James A
authors: JA
authors: Kennedy
authors: 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.
authors: Aaron D
authors: AD
authors: Schimmer
authors: 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.
authors: Andre C
authors: AC
authors: Schuh
authors: 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.
authors: Karen W
authors: KW
authors: Yee
authors: Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada.
authors: Jessica L
authors: JL
authors: McLeod
authors: Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada.
authors: Monica
authors: M
authors: Doedens
authors: Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada.
authors: Jessie J F
authors: JJ
authors: Medeiros
authors: 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.
authors: Rene
authors: R
authors: Marke
authors: Chonnam National University Hwasun Hospital, Genome Research Center for Hematopoietic Diseases, Gwangju 519-809, South Korea.
authors: Hyeoung Joon
authors: HJ
authors: Kim
authors: Chonnam National University Hwasun Hospital, Genome Research Center for Hematopoietic Diseases, Gwangju 519-809, South Korea.
authors: Kwon
authors: K
authors: Lee
authors: 1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada [2] Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors: John D
authors: JD
authors: McPherson
authors: 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.
authors: Thomas J
authors: TJ
authors: Hudson
authors: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors: Andrew M K
authors: AM
authors: Brown
authors: Fouad
authors: F
authors: Yousif
authors: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors: Quang M
authors: QM
authors: Trinh
authors: 1] Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors: Lincoln D
authors: LD
authors: Stein
authors: 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.
authors: Mark D
authors: MD
authors: Minden
authors: 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.
authors: Jean C Y
authors: JC
authors: Wang
authors: 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.
authors: John E
authors: JE
authors: Dick
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D019070:Cell Lineage; D002999:Clone Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D064593:Heterografts; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D012074:Remission Induction; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A