Mutations in the load

Bone marrow donors have transferred their pathogenic mutations to recipients

Polina Loseva, N+1

American scientists have found that every second donor of red bone marrow carries clones of cells with pathogenic mutations in their blood. Most of them successfully move into the recipient's body and strengthen there, simultaneously acquiring new mutations. Theoretically, they can cause adverse effects of transplantation, although there is no official confirmation of this hypothesis yet. The work was published in the journal Science Translational Medicine (Wong et al., Engagement of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation).

Despite the fact that all cells in the human body (with rare exceptions) carry the same genes, over time each accumulates its own unique set of mutations, point differences in the DNA sequence. If a cell has the ability to multiply, then as it divides, it forms a cellular clone – a group of cells that are closer to each other by a set of mutations than to their neighbors in the tissue.

Mutations carried by clone cells are not always harmless. On the contrary, if they give cells some advantage (for example, they allow them to divide or absorb nutrients faster than others), then such a clone can displace its neighbors, other clones, from the tissue. This phenomenon is called cellular competition.

This can happen not only in "hard" tissues, but also in the blood, among the cells of the red bone marrow. Scientists have repeatedly noticed that clones often begin to dominate in the blood of older people, and often they carry potentially pathogenic (in particular, oncogenic) mutations.

It was believed that clonality was not yet manifested in young people. At the same time, donors for bone marrow transplantation are most often young people aged 18-44, but the mortality rate of recipients after such transplants is higher than when donors are elderly relatives of the patient. In addition, transplants often entail many side effects – from inflammation and heart disease (which to a lesser extent may be associated with clones) to blood cancer (which may just be a consequence of the reproduction of pathogenic clones). These facts prompted a group of scientists led by Todd Druley from the University of Washington Medical School to check whether clonality occurs in young donors and, if so, what happens to such clones in the recipient's body.

The researchers selected samples from blood biobanks for 25 donor-recipient pairs, while the pairs were selected so that samples were taken before transplantation and several more times after it. To begin with, the researchers sequenced DNA in the blood cells of 25 donors aged 20-58. Scientists were looking for mutations in 80 genes that may be associated with the development of tumors or other blood diseases.

In one of the donors, they found true clonal dominance – more than 2 percent of all stem cells belonged to the same clone. Another 10 donors showed signs of latent dominance: cells with 19 mutations averaged 0.2 percent. 84 percent of these mutations were potentially pathogenic. In the remaining 14 subjects, no mutations were found in the dominant clones.

The authors did not find any of these mutations in the blood of the recipients before transplantation. However, after examining their blood samples after the procedure, they noticed that absolutely all the clones with mutations had taken root in the body of the new host. 74 percent (14 out of 19) of the mutations persisted a year after the transplant, 13 of them were pathogenic. Scientists did not find any connection between the initial prevalence of the clone in the donor and the final one in the recipient (p=0.105). Moreover, the three clones only strengthened their positions and in the new organism moved from covert dominance to explicit.

The researchers then focused on what was happening in the recipient's body. After studying their blood tests 30, 100 and 365 days after transplantation, they noticed that during this time there were more dominant clones. While they found only 19 mutations in clones in donors, 100 days after the transplant, the recipients – who were supposed to receive the same 19 mutations – already had 33 clonal mutations in total. At the same time, the appearance of new mutations in recipients did not depend on which donor they received blood from – with pathogenic mutations or not.

The authors of the work did not set out to link the number of mutations with the result of transplantation, but just in case, they still checked what different transplants lead to. It turned out that recipients who had at least one clone with a mutation in their body more often developed a graft-versus-host reaction, that is, immune aggression of donor cells. However, since the sample was small, this result was not statistically significant (p=0.17).

Thus, the researchers found that almost half of young donors carry in their blood clones of stem cells with potentially pathogenic mutations. Most of them are transferred to the recipient during transplantation and take root in his body, and this does not depend on their initial amount. Apparently, the detected mutations do give clones some kind of advantage in reproduction.

In addition, transplantation entails an increase in the number of mutant clones in the blood. This is probably because new clones multiply and extremely rare mutations, unnoticeable during primary sequencing, become more frequent. But another scenario is also possible, according to which donor cells begin to actively multiply in a new organism and accumulate completely new mutations. Anyway, researchers have yet to verify whether the donation of mutant clones is really associated with an unfavorable outcome of transplantation or other side effects.

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