RT Journal Article
SR Electronic
T1 Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaax6249
DO 10.1126/scitranslmed.aax6249
VO 12
IS 526
A1 Wong, Wing Hing
A1 Bhatt, Sima
A1 Trinkaus, Kathryn
A1 Pusic, Iskra
A1 Elliott, Kevin
A1 Mahajan, Nitin
A1 Wan, Fei
A1 Switzer, Galen E.
A1 Confer, Dennis L.
A1 DiPersio, John
A1 Pulsipher, Michael A.
A1 Shah, Nirali N.
A1 Sees, Jennifer
A1 Bystry, Amelia
A1 Blundell, Jamie R.
A1 Shaw, Bronwen E.
A1 Druley, Todd E.
YR 2020
UL http://stm.sciencemag.org/content/12/526/eaax6249.abstract
AB Clonal hematopoiesis of indeterminate potential, or CHIP, is characterized by the presence of mutant hematopoietic stem cell clones in the bone marrow without overt signs of disease. However, emerging evidence suggests that this condition, which is more common in older patients, may not be as innocuous as previously thought, with recent studies connecting CHIP to a variety of medical problems. Using state-of-the-art gene sequencing methods, Wong et al. detected potentially pathogenic rare clonal mutations in samples from hematopoietic stem cell donors of various ages and showed that these persisted in the transplant recipients, raising questions about their implications for the recipients’ health outcomes.Clonal hematopoiesis is associated with various age-related morbidities. Error-corrected sequencing (ECS) of human blood samples, with a limit of detection of ≥0.0001, has demonstrated that nearly every healthy individual >50 years old harbors rare hematopoietic clones below the detection limit of standard high-throughput sequencing. If these rare mutations confer survival or proliferation advantages, then the clone(s) could expand after a selective pressure such as chemotherapy, radiotherapy, or chronic immunosuppression. Given these observations and the lack of quantitative data regarding clonal hematopoiesis in adolescents and young adults, who are more likely to serve as unrelated hematopoietic stem cell donors, we completed this pilot study to determine whether younger adults harbored hematopoietic clones with pathogenic mutations, how often those clones were transferred to recipients, and what happened to these clones over time after transplantation. We performed ECS on 125 blood and marrow samples from 25 matched unrelated donors and recipients. Clonal mutations, with a median variant allele frequency of 0.00247, were found in 11 donors (44%; median, 36 years old). Of the mutated clones, 84.2% of mutations were predicted to be molecularly pathogenic and 100% engrafted in recipients. Recipients also demonstrated de novo clonal expansion within the first 100 days after hematopoietic stem cell transplant (HSCT). Given this pilot demonstration that rare, pathogenic clonal mutations are far more prevalent in younger adults than previously appreciated, and they engraft in recipients and persist over time, larger studies with longer follow-up are necessary to correlate clonal engraftment with post-HSCT morbidity.