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

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. Individ-uals 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 het-erogeneity 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.

Automated summary

Somatic mutations in hematopoietic stem cells (HSCs) can lead to clonal hematopoiesis (CH) and the production of mutated immune cells, increasing the risk of leukemia and inflammatory diseases. Through genetic engineering and transplantation, researchers found that loss of the TET2 gene in human HSCs resulted in abnormal development and function of neutrophils, leading to heightened inflammatory responses and compact chromatin structure. These findings provide insights into detecting TET2-CH and preventing CH-associated pathologies mediated by neutrophil extracellular traps (NET).