Division of Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, 4515 McKinley Avenue, St. Louis, MO 63110, USA.
Sci Transl Med. 2020 Jan 15;12(526). doi: 10.1126/scitranslmed.aax6249.
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.
克隆性造血与各种与年龄相关的疾病有关。对人类血液样本进行纠错测序（ECS），检测限≥0.0001，结果表明，几乎每个>50 岁的健康个体都存在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，那么在化疗、放疗或慢性免疫抑制等选择性压力下，克隆（s）可能会扩增。鉴于这些观察结果以及缺乏青少年和年轻人克隆性造血的定量数据，他们更有可能作为无关造血干细胞供体，我们完成了这项试点研究，以确定年轻成年人是否存在具有致病性突变的造血克隆，这些克隆在多大程度上经常被转移给受者，以及在移植后随着时间的推移这些克隆会发生什么变化。我们对 25 对匹配的无关供者和受者的 125 份血液和骨髓样本进行了 ECS。在 11 名供者（44%；中位数年龄为 36 岁）中发现了克隆性突变，其变异等位基因频率中位数为 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%在受者中植入。受者在造血干细胞移植（HSCT）后 100 天内也表现出新的克隆性扩张。鉴于这项试点研究表明，在年轻成年人中，罕见的致病性克隆突变比以前认为的更为普遍，并且它们在受者中植入并随着时间的推移持续存在，因此需要进行更大规模的研究并进行更长时间的随访，以将克隆植入与 HSCT 后发病率相关联。
