The Francis Crick Institute
Browse
1-s2.0-S1934590923001741-main.pdf (7.48 MB)

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

Download (7.48 MB)
journal contribution
posted on 2023-06-05, 11:04 authored by 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
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.

Funding

Crick (Grant ID: CC2027, Grant title: Bonnet CC2027) Crick (Grant ID: CC2089, Grant title: Papayannnopoulos CC2089) Crick (Grant ID: CC1076, Grant title: STP Electron Microscopy) Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics) Crick (Grant ID: CC1069, Grant title: STP Light Microscopy) Wellcome Trust (Grant ID: 222825/Z/21/Z, Grant title: WT 222825/Z/21/Z) Crick (Grant ID: CC2090, Grant title: Reis e Sousa CC2090)

History