Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo.
Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs in vivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Petter S
PS
Woll
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 65 Stockholm, Sweden.
Una
U
Kjällquist
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Onima
O
Chowdhury
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Helen
H
Doolittle
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA Cambridge, UK.
David C
DC
Wedge
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Supat
S
Thongjuea
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 65 Stockholm, Sweden.
Rikard
R
Erlandsson
Ludwig Institute for Cancer Research and Department of Cell and Molecular Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
Mtakai
M
Ngara
Department of Cellular Therapy, Norwegian Radium Hospital, Oslo University Hospital, 0130 Oslo, Norway.
Kristina
K
Anderson
Ludwig Institute for Cancer Research and Department of Cell and Molecular Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
Qiaolin
Q
Deng
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Adam J
AJ
Mead
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Laura
L
Stenson
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Alice
A
Giustacchini
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Sara
S
Duarte
Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Eleni
E
Giannoulatou
Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Stephen
S
Taylor
Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
Mohsen
M
Karimi
Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
Christian
C
Scharenberg
Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
Teresa
T
Mortera-Blanco
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Iain C
IC
Macaulay
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Sally-Ann
SA
Clark
Department of Hematology, Oslo University Hospital, Rikshospitalet, 0130 Oslo, Norway.
Ingunn
I
Dybedal
Department of Cellular Therapy, Norwegian Radium Hospital, Oslo University Hospital, 0130 Oslo, Norway.
Dag
D
Josefsen
Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris (AP-HP), Service d'hématologie clinique, 93000 Bobigny, France.
Pierre
P
Fenaux
Department of Hematology, Aarhus University Hospital, 8000 Aarhus, Denmark.
Peter
P
Hokland
Department of Hematology, Aarhus University Hospital, 8000 Aarhus, Denmark.
Mette S
MS
Holm
Department of Molecular Medicine, University of Pavia, and Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
Mario
M
Cazzola
Department of Molecular Medicine, University of Pavia, and Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
Luca
L
Malcovati
Division of Medical Sciences, University of Dundee, Dundee DD1 9SY, Scotland, UK.
Sudhir
S
Tauro
St. James Institute of Oncology, St. James Hospital, Leeds LS9 7TF, UK.
David
D
Bowen
Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DU, UK.
Jacqueline
J
Boultwood
Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DU, UK.
Andrea
A
Pellagatti
Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Sydney 2052, Australia.
John E
JE
Pimanda
Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Sydney 2052, Australia.
Ashwin
A
Unnikrishnan
MRC Molecular Haematology Unit, Department of Haematology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Oxford University Hospital, NHS Trust, Oxford OX3 9DU, UK.
Paresh
P
Vyas
Institute of Cell and Molecular Pathology, Hannover Medical School, 30625 Hannover, Germany.
Gudrun
G
Göhring
Institute of Cell and Molecular Pathology, Hannover Medical School, 30625 Hannover, Germany.
Brigitte
B
Schlegelberger
Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
Magnus
M
Tobiasson
Department of Cellular Therapy, Norwegian Radium Hospital, Oslo University Hospital, 0130 Oslo, Norway.
Gunnar
G
Kvalheim
Ludwig Institute for Cancer Research and de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
Stefan N
SN
Constantinescu
MRC Molecular Haematology Unit, Department of Haematology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Claus
C
Nerlov
Skåne University Hospital, Lund 221 00, Sweden.
Lars
L
Nilsson
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA Cambridge, UK.
Peter J
PJ
Campbell
Ludwig Institute for Cancer Research and Department of Cell and Molecular Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
Rickard
R
Sandberg
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA Cambridge, UK.
Elli
E
Papaemmanuil
Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
Eva
E
Hellström-Lindberg
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 65 Stockholm, Sweden.
Sten
S
Linnarsson
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Departments of Cell and Molecular Biology, Medicine Huddinge, and Laboratory Medicine, Huddinge, Karolinska Institutet and Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden. Electronic address: sten.jacobsen@imm.ox.ac.uk.
Sten Eirik W
SE
Jacobsen
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D011379:Prognosis
D015703:Antigens, CD