Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia-Reference-Cited by-同舟云学术

Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia

Published:2021-01-08 Issue:2 Volume:218 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Louka Eleni¹²^ORCID,Povinelli Benjamin¹²,Rodriguez-Meira Alba¹²^ORCID,Buck Gemma¹²³^ORCID,Wen Wei Xiong¹²⁴^ORCID,Wang Guanlin¹²⁴^ORCID,Sousos Nikolaos¹²^ORCID,Ashley Neil¹²^ORCID,Hamblin Angela⁵^ORCID,Booth Christopher A.G.¹²^ORCID,Roy Anindita²³^ORCID,Elliott Natalina²³^ORCID,Iskander Deena⁶^ORCID,de la Fuente Josu⁷^ORCID,Fordham Nicholas¹²^ORCID,O’Byrne Sorcha²³^ORCID,Inglott Sarah⁸^ORCID,Norfo Ruggiero¹²^ORCID,Salio Mariolina⁹^ORCID,Thongjuea Supat⁴^ORCID,Rao Anupama⁸^ORCID,Roberts Irene²³⁵^ORCID,Mead Adam J.¹²⁵^ORCID

Affiliation:

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

4. MRC WIMM Centre for Computational Biology, University of Oxford, Oxford, UK

5. National Institute of Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK

6. Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK

7. Department of Paediatric Haematology and Bone Marrow Transplantation, St Mary’s Hospital, Imperial College London, London, UK

8. Department of Haematology, Great Ormond Street Hospital National Health Service Foundation Trust, London, UK

9. MRC Human Immunology Unit, WIMM, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

Abstract

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.

Funder

Medical Research Council

Cancer Research UK

NIHR

MRC

Oxford University Hospitals NHS Trust

University of Oxford

Bloodwise

Kay Kendall Leukaemia Fund

Weatherall Institute of Molecular Medicine

NIHR Oxford Biomedical Research Centre

John Fell Fund