Perturbed hematopoietic stem and progenitor cell hierarchy in myelodysplastic syndromes patients with monosomy 7 as the sole cytogenetic abnormality.
The stem and progenitor cell compartments in low- and intermediate-risk myelodysplastic syndromes (MDS) have recently been described, and shown to be highly conserved when compared to those in acute myeloid leukemia (AML). Much less is known about the characteristics of the hematopoietic hierarchy of subgroups of MDS with a high risk of transforming to AML. Immunophenotypic analysis of immature stem and progenitor cell compartments from patients with an isolated loss of the entire chromosome 7 (isolated -7), an independent high-risk genetic event in MDS, showed expansion and dominance of the malignant -7 clone in the granulocyte and macrophage progenitors (GMP), and other CD45RA+ progenitor compartments, and a significant reduction of the LIN-CD34+CD38low/-CD90+CD45RA- hematopoietic stem cell (HSC) compartment, highly reminiscent of what is typically seen in AML, and distinct from low-risk MDS. Established functional in vitro and in vivo stem cell assays showed a poor readout for -7 MDS patients irrespective of marrow blast counts. Moreover, while the -7 clone dominated at all stages of GM differentiation, the -7 clone had a competitive disadvantage in erythroid differentiation. In azacitidine-treated -7 MDS patients with a clinical response, the decreased clonal involvement in mononuclear bone marrow cells was not accompanied by a parallel reduced clonal involvement in the dominant CD45RA+ progenitor populations, suggesting a selective azacitidine-resistance of these distinct -7 progenitor compartments. Our data demonstrate, in a subgroup of high risk MDS with monosomy 7, that the perturbed stem and progenitor cell compartments resemble more that of AML than low-risk MDS.
Center for Hematology and Regenerative Medicine, Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Marios
M
Dimitriou
Center for Hematology and Regenerative Medicine, Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.|Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Petter S
PS
Woll
Center for Hematology and Regenerative Medicine, Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Teresa
T
Mortera-Blanco
Center for Hematology and Regenerative Medicine, Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Mohsen
M
Karimi
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.|Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Wellcome Trust Centre for Human Genetics Oxford, United Kingdom.
David C
DC
Wedge
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Helen
H
Doolittle
Center for Hematology and Regenerative Medicine, Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Iyadh
I
Douagi
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.|Computational Oncology, Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Institute, New York, NY, United States of America.
Elli
E
Papaemmanuil
Center for Hematology and Regenerative Medicine, Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.|Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Sten Eirik W
SE
Jacobsen
Center for Hematology and Regenerative Medicine, Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Eva
E
Hellström-Lindberg
D015703:Antigens, CD / Q000378:metabolism; D001374:Azacitidine / Q000494:pharmacology; D015415:Biomarkers; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7; D005260:Female; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism
D015703:Antigens, CD; D015415:Biomarkers; D001374:Azacitidine
azacitidine; cancer stem cells; monosomy 7; myelodysplastic syndrome; myeloid leukemia
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