Clonal hematopoiesis in frequent whole blood donors

Abstract Healthy volunteer donors are committed to contributing key medical resources. Repeated, regular donation of whole blood represents a specific trigger of hematopoietic stress. Hematopoietic stem cells (HSCs) are known to respond to environmental triggers by altering their differentiation and/or proliferative behavior. This can manifest in long-term changes in the clonal dynamics of HSCs, such as the age-associated expansion of HSCs carrying somatic mutations in genes associated with hematologic cancers—that is, clonal hematopoiesis (CH). A recent study revealed a higher prevalence of CH in frequent donors driven by low-risk mutations in genes encoding for epigenetic modifiers, with DNMT3A and TET2 being the most common. No difference in the prevalence of known preleukemic driver mutations was detected between the cohorts, underscoring the safety of repetitive blood donations. Functional analyses suggest a link between the presence of selected DNMT3A mutations found in the frequent donor group and the responsiveness of the cells to the molecular mediator of bleeding stress, erythropoietin (EPO), but not inflammation. These findings define EPO as one of the environmental factors that provide a fitness advantage to specific mutant HSCs. Analyzing CH prevalence and characteristics in other donor cohorts will be important to comprehensively assess the health risks associated with the different types of donation.