Clonal hematopoiesis in donors and long-term survivors of related allogeneic hematopoietic stem cell transplantation.

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Clonal hematopoiesis is associated with age and an increased risk of myeloid malignancies, cardiovascular risk and all-cause mortality. We tested presence of CH (defined as VAF ≥0.01 in granulocytes using a next-generation DNA sequencing panel targeting 102 genes) in a setting where hematopoietic stem cells (HSCs) of the same individual are exposed to different degrees of proliferative stress and environments, i.e. in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their respective related donors (n=42 donor-recipient pairs). With a median follow-up time since allo-HSCT of 16 years (range: 10-32 years), we found a total of 35 mutations in 23/84 (27.4%) study participants. 10/42 (23.8%) donors, and 13/42 (31%) recipients had CH. CH was associated with older donor and recipient age. We identified five cases of donor-engrafted CH, with one case progressing into myelodysplastic syndrome in both donor and recipient. 4/5 cases showed increased clone size in recipients compared with donors. We further characterized the hematopoietic system in individuals with CH: i) CH was consistently present in myeloid cells but varied in penetrance in B and T cells; ii) colony-forming units (CFUs) revealed clonal evolution or multiple independent clones in individuals with multiple CH mutations; iii) while telomere shortening determined in granulocytes suggested about 20 years of added proliferative history of HSCs in recipients compared with their donors, telomere length in CH versus non-CH CFUs showed varying patterns. This study provides insight into the long-term behavior of the same human HSCs and respective CH development under different proliferative conditions.

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