Beneficial genetic changes observed in regular blood donors

Researchers have identified genetic changes in blood stem cells from frequent blood donors that support the production of new, non-cancerous cells.

Understanding the differences in the mutations that accumulate in our blood stem cells as we age is important to understand how and why blood cancers develop and hopefully how to intervene before the onset of clinical symptoms.

As we age, stem cells in the bone marrow naturally accumulate mutations and with this, we see the emergence of clones, which are groups of blood cells that have a slightly different genetic makeup. Sometimes, specific clones can lead to blood cancers like leukemia.

When people donate blood, stem cells in the bone marrow make new blood cells to replace the lost blood and this stress drives the selection of certain clones.

In research published Blood, the research team analyzed blood samples taken from over 200 frequent donors—people who had donated blood three times a year over 40 years, more than 120 times in total—and sporadic control donors who had donated blood less than five times in total.

Samples from both groups showed a similar level of clonal diversity, but the makeup of the blood cell populations was different.

For instance, both sample groups contained clones with changes to a gene called DNMT3A, which is known to be mutated in people who develop leukemia. Interestingly, the changes to this gene observed in frequent donors were not in the areas known to be preleukemic.

To understand this better, the  researchers edited DNMT3A in human stem cells in the lab. They induced the genetic changes associated with leukemia and also the non-preleukemic changes observed in the frequent donor group.

They grew these cells in two environments: one containing erythropoietin (EPO), a hormone that stimulates red blood cell production which is increased after each blood donation, and another containing inflammatory chemicals to replicate an infection.

The cells with the mutations commonly seen in frequent donors responded and grew in the environment containing EPO and failed to grow in the inflammatory environment. The opposite was seen in the cells with mutations known to be preleukemic.

This suggests that the DNMT3A mutations observed in frequent donors are mainly responding to the physiological blood loss associated with blood donation.

Finally, the team transplanted the human stem cells carrying the two types of mutations into mice. Some of these mice had blood removed and then were given EPO injections to mimic the stress associated with blood donation.

The cells with the frequent donor mutations grew normally in control conditions and promoted red blood cell production under stress, without cells becoming cancerous. In sharp contrast, the preleukemic mutations drove a pronounced increase in white blood cells in both control or stress conditions.

The researchers believe that regular blood donation is one type of activity that selects for mutations that allow cells to respond well to blood loss, but does not select the preleukemic mutations associated with blood cancer.

Karpova, D. et al. Clonal Hematopoiesis Landscape in Frequent Blood Donors, Blood (2025). DOI: 10.1182/blood.2024027999