TY - JOUR
T1 - Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation
AU - Wong, Wing Hing
AU - Bhatt, Sima
AU - Trinkaus, Kathryn
AU - Pusic, Iskra
AU - Elliott, Kevin
AU - Mahajan, Nitin
AU - Wan, Fei
AU - Switzer, Galen E.
AU - Confer, Dennis L.
AU - DiPersio, John
AU - Pulsipher, Michael A.
AU - Shah, Nirali N.
AU - Sees, Jennifer
AU - Bystry, Amelia
AU - Blundell, Jamie R.
AU - Shaw, Bronwen E.
AU - Druley, Todd E.
N1 - Funding Information:
The genomic portion of this study was supported by NCI R01CA211711 to T.E.D., the Hyundai Quantum Award to T.E.D., the Leukemia and Lymphoma Society Scholar Award to T.E.D., the Eli Seth Matthews Leukemia Foundation to T.E.D., and the Kellsie's Hope Foundation to T.E.D. The CIBMTR is supported by Public Health Service Grant/ Cooperative Agreement 5U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); Grant/Cooperative Agreement 1U24HL138660 from NHLBI and NCI; contract HHSH250201700006C with Health Resources and Services Administration (HRSA/DHHS); and three grants (N00014-17-1-2388, N00014-17-1-2850, and N00014-18-1-2045) from the Office of Naval Research. J.R.B. is supported by a UKRI future leaders fellowship and by a CRUK Cambridge Centre Early Detection Programme group leader grant
Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
PY - 2020/1/15
Y1 - 2020/1/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85077940948&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aax6249
DO - 10.1126/scitranslmed.aax6249
M3 - Article
C2 - 31941826
AN - SCOPUS:85077940948
SN - 1946-6234
VL - 12
JO - Science translational medicine
JF - Science translational medicine
IS - 526
M1 - eaax6249
ER -