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.

中文翻译：

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在不相关的造血干细胞移植中植入罕见的致病性供体造血突变。


克隆造血与各种与年龄相关的疾病有关。人类血液样本的纠错测序 (ECS) 检测限≥0.0001，已证明几乎每个 50 岁以上的健康个体都含有低于标准高通量测序检测限的罕见造血克隆。如果这些罕见突变赋予生存或增殖优势，那么克隆可以在化疗、放疗或慢性免疫抑制等选择性压力后扩增。鉴于这些观察结果以及缺乏有关青少年和年轻人（他们更有可能成为不相关的造血干细胞供体）克隆造血的定量数据，我们完成了这项初步研究，以确定年轻人是否携带带有致病性突变的造血克隆，发生频率如何这些克隆被转移给受体，以及移植后这些克隆随着时间的推移发生了什么变化。我们对来自 25 名匹配的无关捐赠者和接受者的 125 份血液和骨髓样本进行了 ECS。在 11 名捐赠者（44%；中位年龄 36 岁）中发现了克隆突变，中位变异等位基因频率为 0.00247。在突变克隆中，84.2% 的突变被预测为分子致病性，并且 100% 被植入受体体内。受者还在造血干细胞移植 (HSCT) 后的前 100 天内表现出从头克隆扩增。鉴于这一试点表明，罕见的致病性克隆突变在年轻人中比以前认识的更为普遍，并且它们会在受体中植入并随着时间的推移而持续存在，因此有必要进行更大规模的研究和更长时间的随访，以将克隆植入与 HSCT 后发病率联系起来。