How Regular Blood Donors Shape Their Stem Cell Genetics

Researchers at the Francis Crick Institute have identified genetic adaptations in blood stem cells of frequent blood donors that support the production of new, non-cancerous cells. The study, published in Blood, examined how repeated blood donation influences the genetic landscape of stem cells in the bone marrow.

As people age, mutations naturally accumulate in blood stem cells, leading to the formation of genetically distinct groups of blood cells called clones. In some cases, these clones contribute to the development of blood cancers such as leukemia. However, regular blood donation places physiological stress on stem cells, requiring them to regenerate lost blood, which may influence which clones become dominant.

Analysing blood samples from frequent donors

The researchers analyzed blood samples from more than 200 individuals who had donated blood over 120 times in a 40-year period, comparing them to sporadic donors who had donated less than five times. While both groups displayed similar levels of clonal diversity, their blood cell populations had distinct genetic profiles.

Mutations in DNMT3A, a gene commonly altered in leukemia, were observed in both donor groups. However, the mutations present in frequent donors were in regions of the gene not previously associated with leukemia.

To further explore these findings, the team introduced both leukemic and non-leukemic DNMT3A mutations into human stem cells and examined their behavior in different environments.

Impact of blood loss on stem cell mutations

The genetically modified cells were exposed to erythropoietin (EPO), a hormone that stimulates red blood cell production, and to inflammatory conditions simulating infection. The cells carrying mutations found in frequent donors thrived in the EPO-enriched environment but failed to grow under inflammatory conditions. In contrast, cells with known preleukemic mutations responded differently, expanding in inflammatory conditions rather than in response to EPO.

To assess these mutations in a living system, human stem cells with the two types of mutations were transplanted into mice. Some mice were subjected to blood removal and EPO injections to simulate the physiological stress of blood donation. The cells with frequent donor-associated mutations functioned normally and promoted red blood cell production without developing cancerous properties. In contrast, cells carrying preleukemic mutations led to an overproduction of white blood cells under both normal and stress conditions.

Blood donation and mutation selection

The findings suggest that frequent blood donation may selectively favor stem cells that efficiently respond to blood loss rather than those that contribute to leukemia. However, the researchers caution that their sample size was relatively small and that larger studies are needed to confirm whether blood donation influences the likelihood of preleukemic mutations.

Future research aims to investigate how different types of genetic mutations influence leukemia risk and whether certain mutations could be targeted therapeutically.

Reference: Karpova D, Huerga Encabo H Dr, Donato E, et al. Clonal hematopoiesis landscape in frequent blood donors. Blood. 2025:blood.2024027999. doi: 10.1182/blood.2024027999

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