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Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils

Huerga Encabo, H; Aramburu, IV; Garcia-Albornoz, M; Piganeau, M; Wood, H; Song, A; Ferrelli, A; ... Bonnet, D; + view all (2023) Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils. Cell Stem Cell , 30 (6) 781-799.e9. 10.1016/j.stem.2023.05.004. Green open access

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Abstract

Somatic mutations commonly occur in hematopoietic stem cells (HSCs). Some mutant clones outgrow through clonal hematopoiesis (CH) and produce mutated immune progenies shaping host immunity. Individuals with CH are asymptomatic but have an increased risk of developing leukemia, cardiovascular and pulmonary inflammatory diseases, and severe infections. Using genetic engineering of human HSCs (hHSCs) and transplantation in immunodeficient mice, we describe how a commonly mutated gene in CH, TET2, affects human neutrophil development and function. TET2 loss in hHSCs produce a distinct neutrophil heterogeneity in bone marrow and peripheral tissues by increasing the repopulating capacity of neutrophil progenitors and giving rise to low-granule neutrophils. Human neutrophils that inherited TET2 mutations mount exacerbated inflammatory responses and have more condensed chromatin, which correlates with compact neutrophil extracellular trap (NET) production. We expose here physiological abnormalities that may inform future strategies to detect TET2-CH and prevent NET-mediated pathologies associated with CH.

Type: Article
Title: Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.stem.2023.05.004
Publisher version: https://doi.org/10.1016/j.stem.2023.05.004
Language: English
Additional information: © 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Clonal hematopoiesis, TET2, hematopoietic stem and progenitor cells, CRISPR, immune system, preleukemic neutrophil
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/10171213
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