Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging.

Autor:	Jakobsen NA; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK; Oxford Centre for Haematology, NIHR Oxford Biomedical Research Centre, Oxford, UK., Turkalj S; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK; Oxford Centre for Haematology, NIHR Oxford Biomedical Research Centre, Oxford, UK., Zeng AGX; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada., Stoilova B; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Metzner M; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Rahmig S; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Nagree MS; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Shah S; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Moore R; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Usukhbayar B; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Angulo Salazar M; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Gafencu GA; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Kennedy A; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK; Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Newman S; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK; Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Kendrick BJL; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK; Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Taylor AH; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK; Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Afinowi-Luitz R; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK; Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Gundle R; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK; Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Watkins B; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK., Wheway K; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK., Beazley D; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK., Murison A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Aguilar-Navarro AG; Unidad de Investigación Médica en Enfermedades Oncológicas, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico., Flores-Figueroa E; Unidad de Investigación Médica en Enfermedades Oncológicas, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico., Dakin SG; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK., Carr AJ; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK; Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Nerlov C; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Dick JE; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada., Xie SZ; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Vyas P; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK; Oxford Centre for Haematology, NIHR Oxford Biomedical Research Centre, Oxford, UK; Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. Electronic address: paresh.vyas@imm.ox.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell stem cell [Cell Stem Cell] 2024 Aug 01; Vol. 31 (8), pp. 1127-1144.e17. Date of Electronic Publication: 2024 Jun 24.
DOI:	10.1016/j.stem.2024.05.010
Abstrakt:	Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3A and TET2 genes, conferring a competitive advantage through mechanisms that remain unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on human CH bone marrow (BM) samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A- and TET2-mutant clones expand further in early progenitors, while TET2 mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared with HSCs from non-CH samples, revealing a non-cell-autonomous effect. However, DNMT3A- and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are resistant to the deleterious impact of inflammation and aging. Competing Interests: Declaration of interests J.E.D. receives royalties from Trillium Therapeutics Inc./Pfizer and a commercial research grant from Celgene/BMS. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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