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

Hector Huerga Encabo; Iker Valle Aramburu; Manuel Garcia-Albornoz; Marion Piganeau; Henry Wood; Anna Song; Alessandra Ferrelli; Aneesh Sharma; Carlos M Minutti; Marie-Charlotte Domart; Despoina Papazoglou; Kristian Gurashi; Miriam Llorian Sopena; Robert Goldstone; Todd Fallesen; Qian Wang; Linda Ariza-McNaughton; Daniel H Wiseman; Kiran Batta; Rajeev Gupta; Venizelos Papayannopoulos; Dominique Bonnet

doi:10.1016/j.stem.2023.05.004

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

Hector Huerga Encabo, Iker Valle Aramburu, Manuel Garcia-Albornoz, Marion Piganeau, Henry Wood, Anna Song, Alessandra Ferrelli, Aneesh Sharma, Carlos M Minutti, Marie-Charlotte Domart, Despoina Papazoglou, Kristian Gurashi, Miriam Llorian Sopena, Robert Goldstone, Todd Fallesen, Qian Wang, Linda Ariza-McNaughton, Daniel H Wiseman, Kiran Batta, Rajeev GuptaVenizelos Papayannopoulos, Dominique Bonnet

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	781-799.e9
Journal	Cell Stem Cell
Volume	30
Issue number	6
DOIs	https://doi.org/10.1016/j.stem.2023.05.004
Publication status	Published - 1 Jun 2023

Keywords

Humans
Mice
Animals
Neutrophils
Proto-Oncogene Proteins
Hematopoietic Stem Cells/physiology
Bone Marrow
Hematopoiesis/genetics
Mutation
DNA-Binding Proteins/genetics
Dioxygenases/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.stem.2023.05.004Licence: CC BY

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Huerga Encabo, H., Aramburu, I. V., Garcia-Albornoz, M., Piganeau, M., Wood, H., Song, A., Ferrelli, A., Sharma, A., Minutti, C. M., Domart, M.-C., Papazoglou, D., Gurashi, K., Llorian Sopena, M., Goldstone, R., Fallesen, T., Wang, Q., Ariza-McNaughton, L., Wiseman, D. H., Batta, K., ... Bonnet, D. (2023). Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils. Cell Stem Cell, 30(6), 781-799.e9. https://doi.org/10.1016/j.stem.2023.05.004

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title = "Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils",

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.",

keywords = "Humans, Mice, Animals, Neutrophils, Proto-Oncogene Proteins, Hematopoietic Stem Cells/physiology, Bone Marrow, Hematopoiesis/genetics, Mutation, DNA-Binding Proteins/genetics, Dioxygenases/genetics",

author = "{Huerga Encabo}, Hector and Aramburu, {Iker Valle} and Manuel Garcia-Albornoz and Marion Piganeau and Henry Wood and Anna Song and Alessandra Ferrelli and Aneesh Sharma and Minutti, {Carlos M} and Marie-Charlotte Domart and Despoina Papazoglou and Kristian Gurashi and {Llorian Sopena}, Miriam and Robert Goldstone and Todd Fallesen and Qian Wang and Linda Ariza-McNaughton and Wiseman, {Daniel H} and Kiran Batta and Rajeev Gupta and Venizelos Papayannopoulos and Dominique Bonnet",

year = "2023",

month = jun,

day = "1",

doi = "10.1016/j.stem.2023.05.004",

language = "English",

volume = "30",

pages = "781--799.e9",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "6",

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Huerga Encabo, H, Aramburu, IV, Garcia-Albornoz, M, Piganeau, M, Wood, H, Song, A, Ferrelli, A, Sharma, A, Minutti, CM, Domart, M-C, Papazoglou, D, Gurashi, K, Llorian Sopena, M, Goldstone, R, Fallesen, T, Wang, Q, Ariza-McNaughton, L, Wiseman, DH, Batta, K, Gupta, R, Papayannopoulos, V & Bonnet, D 2023, 'Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils', Cell Stem Cell, vol. 30, no. 6, pp. 781-799.e9. https://doi.org/10.1016/j.stem.2023.05.004

TY - JOUR

T1 - Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils

AU - Huerga Encabo, Hector

AU - Aramburu, Iker Valle

AU - Garcia-Albornoz, Manuel

AU - Piganeau, Marion

AU - Wood, Henry

AU - Song, Anna

AU - Ferrelli, Alessandra

AU - Sharma, Aneesh

AU - Minutti, Carlos M

AU - Domart, Marie-Charlotte

AU - Papazoglou, Despoina

AU - Gurashi, Kristian

AU - Llorian Sopena, Miriam

AU - Goldstone, Robert

AU - Fallesen, Todd

AU - Wang, Qian

AU - Ariza-McNaughton, Linda

AU - Wiseman, Daniel H

AU - Batta, Kiran

AU - Gupta, Rajeev

AU - Papayannopoulos, Venizelos

AU - Bonnet, Dominique

PY - 2023/6/1

Y1 - 2023/6/1

N2 - 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.

AB - 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.

KW - Humans

KW - Mice

KW - Animals

KW - Neutrophils

KW - Proto-Oncogene Proteins

KW - Hematopoietic Stem Cells/physiology

KW - Bone Marrow

KW - Hematopoiesis/genetics

KW - Mutation

KW - DNA-Binding Proteins/genetics

KW - Dioxygenases/genetics

U2 - 10.1016/j.stem.2023.05.004

DO - 10.1016/j.stem.2023.05.004

M3 - Article

C2 - 37267914

SN - 1934-5909

VL - 30

SP - 781-799.e9

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 6

ER -

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

Abstract

Keywords

UN SDGs

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