PMID- 24522528
OWN - NLM
STAT- MEDLINE
DCOM- 20140312
LR  - 20220812
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 506
IP  - 7488
DP  - 2014 Feb 20
TI  - Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.
PG  - 328-33
LID - 10.1038/nature13038 [doi]
AB  - 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.
FAU - Shlush, Liran I
AU  - Shlush LI
AD  - 1] Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, 
      Ontario M5G 2M9, Canada [2].
FAU - Zandi, Sasan
AU  - Zandi S
AD  - 1] Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, 
      Ontario M5G 2M9, Canada [2].
FAU - Mitchell, Amanda
AU  - Mitchell A
AD  - Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, 
      Ontario M5G 2M9, Canada.
FAU - Chen, Weihsu Claire
AU  - Chen WC
AD  - Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, 
      Ontario M5G 2M9, Canada.
FAU - Brandwein, Joseph M
AU  - Brandwein JM
AD  - 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.
FAU - Gupta, Vikas
AU  - Gupta V
AD  - 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.
FAU - Kennedy, James A
AU  - Kennedy JA
AD  - Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, 
      Ontario M5G 2M9, Canada.
FAU - Schimmer, Aaron D
AU  - Schimmer AD
AD  - 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.
FAU - Schuh, Andre C
AU  - Schuh AC
AD  - 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.
FAU - Yee, Karen W
AU  - Yee KW
AD  - 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.
FAU - McLeod, Jessica L
AU  - McLeod JL
AD  - Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, 
      Ontario M5G 2M9, Canada.
FAU - Doedens, Monica
AU  - Doedens M
AD  - Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, 
      Ontario M5G 2M9, Canada.
FAU - Medeiros, Jessie J F
AU  - Medeiros JJ
AD  - Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, 
      Ontario M5G 2M9, Canada.
FAU - Marke, Rene
AU  - Marke R
AD  - 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.
FAU - Kim, Hyeoung Joon
AU  - Kim HJ
AD  - Chonnam National University Hwasun Hospital, Genome Research Center for 
      Hematopoietic Diseases, Gwangju 519-809, South Korea.
FAU - Lee, Kwon
AU  - Lee K
AD  - Chonnam National University Hwasun Hospital, Genome Research Center for 
      Hematopoietic Diseases, Gwangju 519-809, South Korea.
FAU - McPherson, John D
AU  - McPherson JD
AD  - 1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 
      2M9, Canada [2] Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, 
      Canada.
FAU - Hudson, Thomas J
AU  - Hudson TJ
AD  - 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.
CN  - HALT Pan-Leukemia Gene Panel Consortium
FAU - Brown, Andrew M K
AU  - Brown AM
AD  - Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
FAU - Yousif, Fouad
AU  - Yousif F
FAU - Trinh, Quang M
AU  - Trinh QM
AD  - Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
FAU - Stein, Lincoln D
AU  - Stein LD
AD  - 1] Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada [2] 
      Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 
      1A8, Canada.
FAU - Minden, Mark D
AU  - Minden MD
AD  - 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.
FAU - Wang, Jean C Y
AU  - Wang JC
AD  - 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.
FAU - Dick, John E
AU  - Dick JE
AD  - 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.
LA  - eng
GR  - 105367-1/Canadian Institutes of Health Research/Canada
GR  - R21 CA152613/CA/NCI NIH HHS/United States
GR  - CSC-105367/CAPMC/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140212
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (DNMT3A protein, human)
RN  - 0 (Dnmt3a protein, mouse)
RN  - 0 (NPM1 protein, human)
RN  - 0 (Npm1 protein, mouse)
RN  - 0 (Nuclear Proteins)
RN  - 117896-08-9 (Nucleophosmin)
RN  - EC 1.1.1.41 (IDH2 protein, human)
RN  - EC 1.1.1.41 (Isocitrate Dehydrogenase)
RN  - EC 1.1.1.42. (IDH1 protein, human)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases)
RN  - EC 2.1.1.37 (DNA Methyltransferase 3A)
SB  - IM
EIN - Nature. 2014 Apr 17;508(7496):420. Yousif, Fouad [added]
CIN - Nature. 2014 Feb 20;506(7488):300-1. PMID: 24522525
CIN - Nat Rev Cancer. 2014 Apr;14(4):212. PMID: 24599218
CIN - Cell Stem Cell. 2014 Apr 3;14(4):421-2. PMID: 24702991
MH  - Animals
MH  - Cell Differentiation
MH  - Cell Division
MH  - Cell Lineage
MH  - Clone Cells/cytology/metabolism/pathology
MH  - DNA (Cytosine-5-)-Methyltransferases/genetics/metabolism
MH  - DNA Methyltransferase 3A
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Female
MH  - Hematopoiesis
MH  - Hematopoietic Stem Cells/*cytology/drug effects/metabolism/pathology
MH  - Heterografts
MH  - Humans
MH  - Isocitrate Dehydrogenase/genetics
MH  - Leukemia, Myeloid, Acute/diagnosis/drug therapy/genetics/*pathology
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Mutation/genetics
MH  - Neoplasm Transplantation
MH  - Neoplastic Stem Cells/*cytology/drug effects/metabolism/pathology
MH  - Nuclear Proteins/genetics
MH  - Nucleophosmin
MH  - Remission Induction
MH  - T-Lymphocytes/metabolism/pathology
PMC - PMC4991939
MID - CAMS3940
OID - NLM: CAMS3940
FIR - Hudson, Thomas J
IR  - Hudson TJ
FIR - Jamieson, Catriona
IR  - Jamieson C
FIR - Frazer, Kelly A
IR  - Frazer KA
FIR - McPherson, John D
IR  - McPherson JD
FIR - Chun, Hye-Jung E
IR  - Chun HJ
FIR - Danska, Jayne S
IR  - Danska JS
FIR - Dick, John E
IR  - Dick JE
FIR - Kipps, Thomas J
IR  - Kipps TJ
FIR - Messer, Karen
IR  - Messer K
FIR - Minden, Mark D
IR  - Minden MD
FIR - Muthuswamy, Lakshmi B
IR  - Muthuswamy LB
FIR - Smith, Erin N
IR  - Smith EN
FIR - Wang, Jean C Y
IR  - Wang JC
FIR - Holt, Carson
IR  - Holt C
FIR - Muthuswamy, Lakshmi B
IR  - Muthuswamy LB
FIR - Yousif, Fouad Y
IR  - Yousif FY
FIR - Brown, Andrew M K
IR  - Brown AM
FIR - McPherson, John D
IR  - McPherson JD
FIR - Beck, Timothy A
IR  - Beck TA
FIR - Bao, Lei
IR  - Bao L
FIR - Claudio, Jaime O
IR  - Claudio JO
FIR - Helm, Michelle Gaasenbeek
IR  - Helm MG
FIR - Kotzer, Amanda
IR  - Kotzer A
FIR - Moniakis, John
IR  - Moniakis J
FIR - Prussak, Charles E
IR  - Prussak CE
FIR - Sadarangani, Anil
IR  - Sadarangani A
FIR - Chiu, Priscilla
IR  - Chiu P
FIR - Eppert, Kolja
IR  - Eppert K
FIR - Guidos, Cynthia J
IR  - Guidos CJ
FIR - Hogge, Donna E
IR  - Hogge DE
FIR - Kowalski, Paul E
IR  - Kowalski PE
FIR - Marra, Marco A
IR  - Marra MA
FIR - Notta, Faiyaz
IR  - Notta F
FIR - Schimmer, Aaron D
IR  - Schimmer AD
FIR - Shlush, Liran
IR  - Shlush L
FIR - Jiang, Bei
IR  - Jiang B
FIR - Mullen, Laura
IR  - Mullen L
FIR - Pasternack, Danielle
IR  - Pasternack D
FIR - Timms, Lee
IR  - Timms L
FIR - Sam, Michelle
IR  - Sam M
EDAT- 2014/02/14 06:00
MHDA- 2014/03/13 06:00
PMCR- 2016/08/19
CRDT- 2014/02/14 06:00
PHST- 2013/08/26 00:00 [received]
PHST- 2014/01/20 00:00 [accepted]
PHST- 2014/02/14 06:00 [entrez]
PHST- 2014/02/14 06:00 [pubmed]
PHST- 2014/03/13 06:00 [medline]
PHST- 2016/08/19 00:00 [pmc-release]
AID - nature13038 [pii]
AID - 10.1038/nature13038 [doi]
PST - ppublish
SO  - Nature. 2014 Feb 20;506(7488):328-33. doi: 10.1038/nature13038. Epub 2014 Feb 12.