ATACSeq of TET2-mutant human HSCs
The expansion of hematopoietic stem cell clones and their immune progeny carrying somatic mutations is defined as clonal hematopoiesis (CH) and its prevalence increases with age. Individuals with CH are at higher risk of developing hematological malignancies as well as other pathologies, such as cardiovascular or inflammatory pulmonary diseases. Understanding the environmental conditions that favor mutant clones and the CH-immune system response to such environments is key to designing therapeutic strategies to stall the expansion of mutant clones and the development of CH-associated pathologies. In this work, we characterized how mutations in TET2, increase the competitive advantage of human HSCs upon environmental stress conditions and simultaneously shape the immune response of their myeloid progeny. Employing a humanized mouse model, we unravel a cell-specific impact of TET2 mutations on HSCs and their myeloid progeny to inflammatory stress. In such environments, TET2Mut HSCs have a mitigated transcriptional upregulation of inflammatory pathways, and by contrast, TET2Mut myeloid cells have an exacerbated inflammatory response. A distinct monocyte-macrophage trajectory derived from TET2Mut HSCs contributes to pathological inflammation. These findings provide evidence at the human cell level and reconcile the notion that TET2-derived CH is associated with both increased stemness in the HSC compartment and inflammation elicited by the myeloid progeny. Overall design: Using CRISPR-edited human HSCs and transplantation in immunodeficient mice, we have sorted CD34+CD38-CD45RA- cells and analyzed the chromatin conformation of TET2 mutant (TET2Mut) HSCs.