Juvenile myelomonocytic leukemia (JMML) is a poor-prognosis childhood leukemia usually caused by RAS-pathway mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), including an aberrant Lin−CD34+CD38−CD90+CD45RA+ population. Single-cell HSPC index-sorting and clonogenic assays show that (1) all somatic mutations can be backtracked to the phenotypic HSC compartment, with RAS-pathway mutations as a “first hit,” (2) mutations are acquired with both linear and branching patterns of clonal evolution, and (3) mutant HSPCs are present after allogeneic HSC transplant before molecular/clinical evidence of relapse. Stem cell assays reveal interpatient heterogeneity of JMML LSCs, which are present in, but not confined to, the phenotypic HSC compartment. RNA sequencing of JMML LSC reveals up-regulation of stem cell and fetal genes (HLF, MEIS1, CNN3, VNN2, and HMGA2) and candidate therapeutic targets/biomarkers (MTOR, SLC2A1, and CD96), paving the way for LSC-directed disease monitoring and therapy in this disease.
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January 08 2021
Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia
Eleni Louka,
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
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Benjamin Povinelli,
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
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Alba Rodriguez-Meira,
Alba Rodriguez-Meira
Data curation, Formal analysis, Investigation, Methodology, Software, Visualization
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
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Gemma Buck,
Gemma Buck
Investigation
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
3
Department of Paediatrics, University of Oxford, Oxford, UK
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Wei Xiong Wen,
Wei Xiong Wen
Data curation, Formal analysis, Software, Validation, Visualization, Writing - review & editing
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
9
MRC WIMM Centre for Computational Biology, University of Oxford, Oxford, UK
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Guanlin Wang,
Guanlin Wang
Formal analysis, Software
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
9
MRC WIMM Centre for Computational Biology, University of Oxford, Oxford, UK
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Nikolaos Sousos,
Nikolaos Sousos
Formal analysis, Investigation, Validation, Writing - review & editing
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
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Neil Ashley,
Neil Ashley
Investigation
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
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Angela Hamblin,
Angela Hamblin
Data curation, Formal analysis, Methodology, Writing - original draft, Writing - review & editing
4
National Institute of Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK
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Christopher A.G. Booth,
Christopher A.G. Booth
Investigation, Validation
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
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Anindita Roy,
Anindita Roy
Formal analysis, Visualization
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
3
Department of Paediatrics, University of Oxford, Oxford, UK
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Natalina Elliott,
Natalina Elliott
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
3
Department of Paediatrics, University of Oxford, Oxford, UK
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Deena Iskander,
Deena Iskander
Investigation, Resources
5
Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK
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Josu de la Fuente,
Josu de la Fuente
Data curation, Investigation, Project administration
6
Department of Paediatric Haematology and Bone Marrow Transplantation, St Mary’s Hospital, Imperial College London, London, UK
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Nicholas Fordham,
Nicholas Fordham
Data curation, Investigation
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
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Sorcha O’Byrne,
Sorcha O’Byrne
Investigation
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
3
Department of Paediatrics, University of Oxford, Oxford, UK
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Sarah Inglott,
Sarah Inglott
Resources
7
Department of Haematology, Great Ormond Street Hospital National Health Service Foundation Trust, London, UK
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Ruggiero Norfo,
Ruggiero Norfo
Formal analysis, Validation
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
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Mariolina Salio,
Mariolina Salio
Formal analysis, Supervision, Validation
8
MRC Human Immunology Unit, WIMM, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
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Supat Thongjuea,
Supat Thongjuea
Formal analysis, Software
9
MRC WIMM Centre for Computational Biology, University of Oxford, Oxford, UK
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Anupama Rao,
Anupama Rao
Conceptualization, Funding acquisition, Project administration, Supervision, Writing - review & editing
7
Department of Haematology, Great Ormond Street Hospital National Health Service Foundation Trust, London, UK
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Irene Roberts,
Conceptualization, Formal analysis, Funding acquisition, Methodology, Resources, Supervision, Visualization, Writing - original draft, Writing - review & editing
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
3
Department of Paediatrics, University of Oxford, Oxford, UK
4
National Institute of Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK
Irene Roberts: irene.roberts@paediatrics.ox.ac.uk
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Adam J. Mead
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
4
National Institute of Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK
Correspondence to Adam J. Mead: adam.mead@imm.ox.ac.uk
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Eleni Louka
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Benjamin Povinelli
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Alba Rodriguez-Meira
Data curation, Formal analysis, Investigation, Methodology, Software, Visualization
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Gemma Buck
Investigation
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
3
Department of Paediatrics, University of Oxford, Oxford, UK
Wei Xiong Wen
Data curation, Formal analysis, Software, Validation, Visualization, Writing - review & editing
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
9
MRC WIMM Centre for Computational Biology, University of Oxford, Oxford, UK
Guanlin Wang
Formal analysis, Software
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
9
MRC WIMM Centre for Computational Biology, University of Oxford, Oxford, UK
Nikolaos Sousos
Formal analysis, Investigation, Validation, Writing - review & editing
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Neil Ashley
Investigation
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Angela Hamblin
Data curation, Formal analysis, Methodology, Writing - original draft, Writing - review & editing
4
National Institute of Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK
Christopher A.G. Booth
Investigation, Validation
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Anindita Roy
Formal analysis, Visualization
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
3
Department of Paediatrics, University of Oxford, Oxford, UK
Natalina Elliott
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
3
Department of Paediatrics, University of Oxford, Oxford, UK
Deena Iskander
Investigation, Resources
5
Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK
Josu de la Fuente
Data curation, Investigation, Project administration
6
Department of Paediatric Haematology and Bone Marrow Transplantation, St Mary’s Hospital, Imperial College London, London, UK
Nicholas Fordham
Data curation, Investigation
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Sorcha O’Byrne
Investigation
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
3
Department of Paediatrics, University of Oxford, Oxford, UK
Sarah Inglott
Resources
7
Department of Haematology, Great Ormond Street Hospital National Health Service Foundation Trust, London, UK
Ruggiero Norfo
Formal analysis, Validation
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Mariolina Salio
Formal analysis, Supervision, Validation
8
MRC Human Immunology Unit, WIMM, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Supat Thongjuea
Formal analysis, Software
9
MRC WIMM Centre for Computational Biology, University of Oxford, Oxford, UK
Anupama Rao
Conceptualization, Funding acquisition, Project administration, Supervision, Writing - review & editing
7
Department of Haematology, Great Ormond Street Hospital National Health Service Foundation Trust, London, UK
Irene Roberts
Conceptualization, Formal analysis, Funding acquisition, Methodology, Resources, Supervision, Visualization, Writing - original draft, Writing - review & editing
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
3
Department of Paediatrics, University of Oxford, Oxford, UK
4
National Institute of Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK
Adam J. Mead
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing
1
Haematopoietic Stem Cell Biology Laboratory, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2
Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, University of Oxford, Oxford, UK
4
National Institute of Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK
Correspondence to Adam J. Mead: adam.mead@imm.ox.ac.uk
Irene Roberts: irene.roberts@paediatrics.ox.ac.uk
*
E. Louka and B. Povinelli contributed equally to this paper.
**
I. Roberts and A.J. Mead contributed equally to this paper.
Received:
May 08 2018
Revision Received:
September 01 2020
Accepted:
November 12 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
Bloodwise
(NO AWARD)
Cancer Research UK
(NO AWARD)
John Fell Fund, University of Oxford
(131/030)
Kay Kendall Leukaemia Fund
(KKL1124)
Medical Research Council
(MR/M026655/1)
National Institute for Health Research
(NO AWARD)
NIHR Oxford Biomedical Research Centre
(NO AWARD)
Oxford University Hospitals NHS Foundation Trust
(NO AWARD)
University of Oxford
(NO AWARD)
© 2021 Louka et al.
2021
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (2): e20180853.
Article history
Received:
May 08 2018
Revision Received:
September 01 2020
Accepted:
November 12 2020
Connected Content
Commentary
Stem cell origins of JMML
Citation
Eleni Louka, Benjamin Povinelli, Alba Rodriguez-Meira, Gemma Buck, Wei Xiong Wen, Guanlin Wang, Nikolaos Sousos, Neil Ashley, Angela Hamblin, Christopher A.G. Booth, Anindita Roy, Natalina Elliott, Deena Iskander, Josu de la Fuente, Nicholas Fordham, Sorcha O’Byrne, Sarah Inglott, Ruggiero Norfo, Mariolina Salio, Supat Thongjuea, Anupama Rao, Irene Roberts, Adam J. Mead; Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia. J Exp Med 1 February 2021; 218 (2): e20180853. doi: https://doi.org/10.1084/jem.20180853
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