When people donate blood, stem cells in the bone marrow make new blood cells to replace what was lost. This stress can drive the selection of certain clones—groups of blood cells with a slightly different genetic makeup than other cells. Now scientists at Francis Crick Institute and their collaborators elsewhere have identified genetic changes in blood stem cells from frequent donors that may support the production of healthy non-cancerous cells.
Details were published in a new paper in the journalBlood titled, “Clonal Hematopoiesis Landscape in Frequent Blood Donors.” This study is part of efforts to deepen scientists’ understanding of the differences in the mutations that accumulate in blood stem cells as people age.Knowing which mutations contribute to blood cancers’ development could help oncologists intervene in patients’ cases sooner before the onset of clinical symptoms.
The Crick researchers in collaboration with colleagues from from DFKZ in Heidelberg and the German Red Cross Blood Donation Center, analyzed blood samples 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.
Their analysis showed that samples from both groups had a similar level of clonal diversity, but the makeup of the blood cell populations was different. Specifically, both sample groups contained clones with changes in the DNMT3A gene, which is known to be mutated in people who can go on to develop blood cancers like leukemia.However, the changes to this gene observed in frequent donors were not located in areas known to be preleukemic.
To understand this better, the Crick 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 then grew these cells in two environments: one containing erythropoietin (EPO), a hormone that stimulates red blood cell production which is typically upregulated after blood donations, 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 but failed to grow in the inflammatory environment. The opposite was seen in the cells with mutations known to be preleukemic. This suggested to the researchers that when these mutations were present in frequent donors, they developed mainly in response to the blood loss associated with donation.
Next, the team transplanted human stem cells with two types of mutations into mice some of which had blood removed. The mice also received EPO injections to mimic the stress associated with donating blood. The stem cells with the mutations that were associated with frequent blood donation grew normalling in control conditions and promoted red blood cell production under stress. In contrast, the cells with mutations in preleukemic regions drove increased white blood cell production under both stress and control conditions.
These findings led the researchers to conclude that regular blood donation may drive the selection of beneficial genetic mutations. Specifically, “activities that put low levels of stress on blood cell production allow our blood stem cells to renew and we think this favors mutations that further promote stem cell growth rather than disease,” said Dominique Bonnet, PhD, senior author on the paper and group leader of the hematopoietic stem cell laboratory at the Crick.
She further noted that the “sample size is quite modest, so we can’t say that blood donation definitely decreases the incidence of preleukemic mutations and we will need to look at these results in much larger numbers of people. It might be that people who donate blood are more likely to be healthy if they’re eligible, and this is also reflected in their blood cell clones. But the insight it has given us into different populations of mutations and their effects is fascinating.”
For their next steps, the researchers plan to study the possible role of these different types of mutations in the development of leukemia and to assess whether they can be targeted therapeutically.