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Clonal Expansion Limited in Stem Cell Transplant Recipients, Even After Long Time

NEW YORK – By tracking mutations in the blood of stem cell donors and recipients over time, a team led by researchers at the Fred Hutchinson Cancer Center has characterized whether hematopoietic cell transplants, which are used to treat blood cancers and other conditions affecting the hematopoietic system, lead to an increase in clonal hematopoiesis (CH).

"After allogeneic hematopoietic cell transplantation (HCT), a very small proportion of donor stem cells must reconstitute the recipient's entire hematopoietic system, a process associated with high replicative demand," first and corresponding author Masumi Ueda Oshima, a researcher affiliated with the Fred Hutchinson Cancer Center and the University of Washington School of Medicine, and her colleagues wrote in a paper published in Science Translational Medicine on Wednesday.

"Historically, there were concerns that donor stem cells may give rise to oligoclonal or even monoclonal hematopoiesis in HCT recipients, which could increase the risk of developing clonal malignant disorders," they explained.

To investigate this possibility, Oshima and colleagues from Fred Hutch, UW, and TwinStrand Biosciences performed ultrasensitive duplex sequencing on blood samples collected from 16 pairs of HCT donors and recipients at different time points ranging from six to 45 years after the procedure.

"With the advantage of ultrasensitive sequencing technology, our data set the foundation for studying clinically relevant questions, such as the impact of donor age and pre-existing donor CH on the long-term outcomes of HCT recipients," the authors wrote, noting that the duplex sequencing approach "detects low-frequency variants that other DNA sequencing methods miss by separately tagging, copying, and sequencing the forward and reverse DNA strands of individual DNA molecules."

With the help of samples collected from donors at the time of the transplant in 11 of the cases, the team was able to compare sequences across donor-recipient pairs over time, searching for signs of clonal hematopoiesis and mutations in myeloid malignancy-related genes as well as in functionally neutral parts of the genome.

All but two of the HCT procedures involved bone marrow transplantation, and 11 of the recipients received HCT to treat malignant disease.

Overall, the team saw comparable mutation rates in the donor and recipient groups, with average mutation rates of 2 percent per year across the myeloid malignancy-linked genes in donors and 2.6 percent per year in the HCT recipients.

When they focused on donor variants that increased in allele frequency by tenfold or more in the corresponding HCT recipients, the researchers identified a relatively small subset of variants, accounting for just 6 percent of the 292 variants considered.

While the results pointed to increasing variant allele frequencies for some shared donor-recipient variants over time, the authors concluded that "there does not appear to be widespread accelerated clonal expansion in the transplanted cells, highlighting the immense regenerative capacity of the human hematopoietic system."

"Although our findings will need to be confirmed in larger studies, the data from this unique cohort demonstrated that there was little difference between aging in the blood cells within the donor and aging of the donor's cells after adoption in the recipient, even after decades," they concluded.