Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation

Abstract

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.

Phylogenetic reconstruction of myeloproliferative neoplasm reveals very early origins and lifelong evolution

“…With more rapid JAK2 V617F clonal expansion (PD7271), mutant cells would have been detectable at age 8yrs at 0.01% cell fraction (13 years prior to diagnosis, Fig.5c). Overall, with sensitive techniques detecting up to 1 in 10,000 aberrant cells 16,30 , we estimate it would have been possible to detect JAK2 V617F across all patients >10 to 40 years before disease presentation, irrespective of the timing of JAK2 V617F acquisition or the final clonal fraction reached (Fig.5d).…”

Clonal Hematopoiesis of Indeterminate Potential as a Novel Risk Factor for Donor-Derived Leukemia

“…One case progressed to MDS. Wong et al. (2020) 25 donor/recipient pairs 20–58/19–69 years allogeneic; unrelated donors No cases reported.…”

“…Unexplained cytopenias were observed in HSCT recipients of CHIP donors, demonstrating that donor clones containing CHIP-associated mutations can be transmitted to transplant recipients and can influence recipient blood cell populations ( Gibson et al., 2017a ). CH is commonly detected in both donors and recipients, and these transmitted clones can expand in recipients ( Boettcher et al., 2020 ; Wong et al., 2020 ). The presence of unexplained cytopenias is more common in recipients with older donors, consistent with a possible role for CHIP in pathogenesis ( Gibson et al., 2017a ).…”

“…It is unclear if the clinical presentation and pathogenesis of DDL differ with age and the mechanisms by which HSPCs bearing CHIP-associated mutations interact with the BM microenvironments of different ages are not known ( Wang et al., 2011 , Wiseman, 2011 ). Recently, CHIP-associated mutations were detected in much younger individuals ( Wong et al., 2020 ). With these younger individuals as donors, efficient engraftment and expansion of clones bearing CHIP-associated mutations were reported, but DDL or GVHD were not observed up to 100 days after transplant.…”

The Safety of a Therapeutic Product Composed of a Combination of Stem Cell Released Molecules From Adipose Mesenchymal Stem Cells and Fibroblasts

“…However, stem cell science is a relatively new science, and therapeutic development using stem cells, even approved stem cell therapies for blood diseases, is in need of a better understanding of mechanisms of action and acute and long-term safety profiles, both for the cells and their released molecules. Approved bone marrow stem cell (BMSC) transplants have many associated risks, including possible induction of cancer [ 8 ], including skin cancer [ 9 ], the transference of cancer cells from the donor to the patient [ 10 ] – given the bone marrow is a site of recirculated cancer cells [ 11 , 12 ] – transference and engraftment of BMSCs with pathogenic mutations [ 13 ], and aging of the tissue in which the implant occurs [ 14 ]. Many factors, which are often overlooked, must be considered when developing stem cell-based therapeutics, including something as fundamental as the choice of stem cell type where adipose mesenchymal stem cells (ADSCs) have many advantages over BMSCs for therapeutic development [ 15 ].…”