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Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging.
Jakobsen, Niels Asger; Turkalj, Sven; Zeng, Andy G X; Stoilova, Bilyana; Metzner, Marlen; Rahmig, Susann; Nagree, Murtaza S; Shah, Sayyam; Moore, Rachel; Usukhbayar, Batchimeg; Angulo Salazar, Mirian; Gafencu, Grigore-Aristide; Kennedy, Alison; Newman, Simon; Kendrick, Benjamin J L; Taylor, Adrian H; Afinowi-Luitz, Rasheed; Gundle, Roger; Watkins, Bridget; Wheway, Kim; Beazley, Debra; Murison, Alex; Aguilar-Navarro, Alicia G; Flores-Figueroa, Eugenia; Dakin, Stephanie G; Carr, Andrew J; Nerlov, Claus; Dick, John E; Xie, Stephanie Z; Vyas, Paresh.
Afiliación
  • 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 add
Cell Stem Cell ; 31(8): 1127-1144.e17, 2024 Aug 01.
Article en En | MEDLINE | ID: mdl-38917807
ABSTRACT
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Envejecimiento / Células Madre Hematopoyéticas / Dioxigenasas / ADN (Citosina-5-)-Metiltransferasas / Hematopoyesis Clonal / ADN Metiltransferasa 3A / Inflamación / Mutación Idioma: En Revista: Cell Stem Cell Año: 2024 Tipo del documento: Article
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Envejecimiento / Células Madre Hematopoyéticas / Dioxigenasas / ADN (Citosina-5-)-Metiltransferasas / Hematopoyesis Clonal / ADN Metiltransferasa 3A / Inflamación / Mutación Idioma: En Revista: Cell Stem Cell Año: 2024 Tipo del documento: Article