Posttransplantation clonal dynamics of hematopoietic stem cells carrying prenatal and early‐life <i>DNMT3A</i> mutations

Clonal hematopoiesis (CH), a prevalent and premalignant state in the elderly, has been detected in young individuals under selective pressures such as hematopoietic cell transplantation (HCT). However, the origin of CH and mutational processes underlying CH driver mutations in young blood systems remain unclear. Here, we used genome-wide somatic mutation profiles to retrospectively trace the origin of <i>DNMT3A</i>-mutant CH in three individuals, 14-41 years after childhood HCT. Both the rate and spectrum of somatic mutations in individuals with posttransplant CH were consistent with normal age-associated mutagenesis. Phylogenetic analysis revealed that <i>DNMT3A</i>-mutant HSPCs were present in the donor before 6.8 years of age, including during fetal development, despite being undetectable with a limit of detection of variant allele frequency of 0.001 at the time of transplantation. These findings were validated by comparing the observed mutations to expected age-dependent mutational signatures. Our results reveal that undetectable <i>DNMT3A</i>-mutant clones in young donors can expand into significant CH clones within decades upon transplantation. The rapid expansion of these clones in this context indicates that specific environmental pressures, rather than solely mutation acquisition, drive the development of CH.