Health Previously unseen mutations in stem cells of young donors can be passed to recipients, study finds By Andrew Joseph @DrewQJoseph
January 15, 2020
AP Photo/David J. Phillip
D octors use stem cell transplants to treat patients with certain cancers or blood disorders. And donors, whose blood or bone marrow is used for the procedures, are typically young, for a variety of reasons.
But a pilot study released Wednesday raised the possibility that such donors are also passing along mutations in stem cells that could lead to health problems for some recipients.
The study found that nearly 45% of younger donors had mutations in the transplanted stem cells that could raise the risk of conditions that are sometimes seen in recipients, a higher rate than presumed. Researchers also reported that some of these mutations persisted and proliferated in the recipients’ bone marrow for at least a year.
What remains unknown is whether those mutations are actually contributing to health problems for recipients.
The study was small, with just 25 donors included — and was not large enough and did not last long enough to determine whether people who received cells with these mutations had worse outcomes after a transplant than recipients who got cells without those mutations. Dr. Todd Druley, the senior author of the paper, which was published in the journal Science Translational Medicine, emphasized that patients should continue to receive these stem cells to treat their leukemias or anemias when recommended.
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Researchers not involved with the study praised its technical prowess, and said it was worth investigating further to see if the transplanted mutations did lead to worse outcomes for recipients — projects that Druley and his colleagues have underway. But they agreed it should not yet change clinical practice.
Donors are already screened to make sure they have a clean bill of health and make for a good “match” for recipients, based on their immune systems. Experts said it would be unrealistic to screen every potential donor for the kinds of mutations Druley and his team found. Those mutations were infrequent, and it wasn’t clear they posed health risks to recipients.
“We know that younger donors are better than older donors. We know that the better the donor the better the outcomes. We don’t know how these ultra-low level mutations affect outcomes at all,” said Dr. Corey Cutler, the medical director of the adult stem cell transplantation program at Dana-Farber Cancer Institute.
Hematopoietic stem cells generate blood and immune cells. They are sometimes transplanted into patients with certain blood or immune disorders or cancers whose own cells have been wiped out by chemotherapy, essentially restocking the recipients with healthy cells.
But recipients of these transplants sometimes experience graft versus host disease (when the transplant attacks the recipient’s tissues), heart or immune conditions, or even secondary cancers. Some experts have suspected these conditions might be caused by mutations in donor stem cells, among other factors. It’s in part why they favor younger donors , who are expected to have fewer mutations than older donors. (Donors from 18 to 44 account for 86% of transplants for unrelated patients. Relatives often make for better donors because they are more likely to be matched to recipients based on immune system molecules.)
Most of these mutations are probably benign. But it’s possible that other mutations not only pose a health risk, but also give their host cells a boost over other cells, helping them proliferate over time. That might mean someone who is 40 could have a bad mutation in one in 5,000 cells, but by the age of 50, it could be in one in 50 cells, Druley explained.
The challenge is detecting those mutations. Standard sequencing technology may pick up mutations if they appear in just a small percentage of cells, but for young donors, it would be like finding the few pebbles in a beach full of sand.
Next-generation sequencing “is good if you want to find a mutation that’s in 20% of cells you’re looking at, or even 5%,” Druley said. “We’re looking at mutations that are one in a thousand, or down to one in ten thousand.”
For the new study, Druley and colleagues trained a more powerful tool they call error-corrected sequencing on the cells of the 25 donors, who ranged from 20 to 58 years old. (Fifty-eight would be considered older donors, but the median age of the donors in the study was 26.) They looked for mutations in 80 genes in particular, including genes that, when mutated, are associated with leukemia.
What they found: 11 donors had a collective 19 mutations that were not picked up by standard sequencing technology — 16 of which were “pathogenic,” meaning disease causing.
The researchers also studied the recipients, finding that 14 of the 19 mutations had “engrafted,” or been taken up by the recipient and started to generate other cells, and were still there a year after the transplant. Thirteen of these mutations were pathogenic.
Researchers said it made sense that younger adults had these types of mutations, even if scientists hadn’t previously been able to spot them.
It’s known that mutations accumulate over time, said Dr. Ross Levine, a leukemia specialist at Memorial Sloan Kettering Cancer Center, who was not involved in the new study. “The question has always been in other scenarios if you can detect these clones at earlier or in different contexts, and if they mean anything.”
The new study was not set up to answer that last question.
“That’s the next phase of this research,” Druley said. “Some of these mutations, if they’re going to have an effect, may not have an effect for many, many years. And we had a small population. So we didn’t have enough numbers or enough time.”
Outside researchers said that if these stem cell mutations do contribute to diseases once transferred to recipients, it might take so long or happen so infrequently that it would be difficult to study. Dana-Farber’s Cutler said that, for example, cases of donor-derived leukemia — when the recipient develops blood cancer after a transplant — occur in less than 1% of transplants from unrelated donors.
If the mutations do increase the likelihood of complications in recipients, then why aren’t they posing a problem for the donors themselves? That might also be tied to the prevalence of these mutations, the researchers said.
In donors, these mutations might appear in, say, 1% of cells, and there is competition among cells of all different types of genetic variants to multiply. Plus, donors have healthy immune systems that can help suppress bad actors.
But if cells with these mutations make their way into recipients who have had their own cells blasted away with chemotherapy, it’s a new race. The mutations might give them some advantage to multiply faster than other cells that were transplanted. And as the percentage of cells with these mutations rises, they might be more likely to cause disease.
“When you have these mutations in a host, it may take decades for them to expand to the point of causing issues,” Levine said. In a recipient, however, “it’s almost like you’ve reset the playing field.”
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