Healthy young individuals can carry mutations in their blood stem cells that transfer to recipients of blood stem cell transplants, a new pilot study of 25 pairs of donors and recipients shows. The study is detailed in the Jan. 15 issue of Science Translational Medicine.
These mutations, which have been linked to serious conditions such as graft-versus-host disease in transplant recipients, previously went undetected in the young population of stem cell donors. The preliminary results, based on more sensitive sequencing technologies, imply that blood stem cell mutations may be more common in donors under the age of 50 than previously suspected.
Transplants of blood stem cells — which include bone marrow transplants — can treat or even cure blood-related diseases such as enzyme deficiencies and some anemias. They have also emerged as promising therapies for blood cancers such as multiple myeloma and some types of leukemia, according to the National Cancer Institute.
The study authors stress that their findings are preliminary, and that more research will be needed to tease out any implications for the health of people receiving stem cell transplants. If verified, their discovery might support the potential benefit of adopting more sensitive sequencing techniques to survey these mutations in young donors of stem cells.
Patients who receive stem cell transplants often must deal with various complications in both the short term and long term, according to the study. These complications can range from heart problems to graft-versus-host disease — a disorder where the donated cells attack the recipient's body.
Research has shown that individuals over the age of 50 have accumulated at least some mutations in blood stem cells, a process referred to as clonal hematopoiesis. Clonal mutations don't lead to immediate signs of disease, but some scientists have theorized that they might contribute to the complications seen in transplant recipients.
Prior to 2019, the link between clonal mutations in blood cells and complications in bone marrow transplants was mostly anecdotal, said Todd Druley, associate professor of pediatrics at the Washington University School of Medicine and senior author of the new study.
However, in 2019 a study demonstrated that transfers of clonal mutants from an older, related donor correlated with chronic graft-versus-host disease in the recipient, said Druley.
The discovery encouraged Wing Hing Wong, a graduate student at the Washington University School of Medicine, and colleagues to examine the possibility that clonal mutations might exist in young donors aged 18 to 44 years old, who make up 86% of eligible unrelated stem cell donors. This population almost never displays clonal mutations when examined with standard sequencing techniques, but some researchers suspect young donors may harbor mutations that evade detection.
To hunt down any rogue, undetected clonal mutations, the authors used an advanced sequencing method called error-corrected sequencing, which has a sensitivity for mutations as rare as one in ten thousand, according to Druley. They then analyzed blood and bone marrow samples from 25 matched, unrelated donors and recipients of stem cell transplants.
The scientists discovered that 11 of the donors, with a median age of 26, had clonal mutations that couldn't be detected with standard sequencing techniques. Furthermore, subsequent experiments predicted that 84% of these mutations could be disease-causing.
Importantly, all of the mutations transferred to the patients who received the stem cell transplants, and the clones expanded in the patients in the first 100 days after transplantation.
"Essentially, we show that healthy people, unaffected by these mutations, transfer these mutations — 100% of the time — to recipients who are not healthy due to weeks or months of chemotherapy, radiation, immune system suppression and antibiotics," said Druley.
He emphasized that the clinical implications of this study are still unclear, as any definitive conclusions would require more long-term research in a larger group of patients. However, there is preliminary evidence that the transfer of these clones may be linked to common transplant complications such as graft-versus-host disease, as well as more rare consequences such as donor-derived leukemia, he said.
"Once we have a more comprehensive study, we might need to carefully screen donors for mutations that are otherwise undetectable, but are associated with clinical complications in recipients," the authors said.
When asked about the difficulty of adopting more stringent sequencing methods, Druley said the sequencing technique is straightforward to implement. He noted that the technique is already being offered as a service by at least one life sciences company, which licensed the technology.
Druley added that the group's goal is certainly not to cull the pool of available young donors by excluding those who might harbor these mutations. Rather, he foresees a scenario where advanced sequencing could be used to screen several potential donors, and select one who may be best suited for the recipient.
"These results should not be taken as a red flag to reduce one's willingness to donate or to receive a hematopoietic stem cell donation," he said. "Rather, this can be used as another tool for surveillance and, if necessary, earlier intervention due to an increased risk — not a certainty — of any of the potential complications."
The scientists are collaborating with the National Marrow Donor Program to conduct larger, retrospective studies of recipients whose outcomes are well-known, as well as prospective studies to examine the possible benefits of more frequent surveillance in recipients.
"We hope these projects will provide greater resolution as to the role of clonal hematopoietic profiling in stem cell transplant recipients," the authors said.