Genetic instability is a major concern for successful application of stem cells in regenerative medicine. However, the mutational consequences of the most applied stem cell therapy in humans, hematopoietic stem cell transplantation (HSCT), remain unknown. Here we characterized the mutation burden of hematopoietic stem and progenitor cells (HSPCs) of human HSCT recipients and their donors using whole-genome sequencing. We demonstrate that the majority of transplanted HSPCs did not display altered mutation accumulation. However, in some HSCT recipients, we identified multiple HSPCs with an increased mutation burden after transplantation. This increase could be attributed to a unique mutational signature caused by the antiviral drug ganciclovir. Using a machine learning approach, we detected this signature in cancer genomes of individuals who received HSCT or solid organ transplantation earlier in life. Antiviral treatment with nucleoside analogs can cause enhanced mutagenicity in transplant recipients, which may ultimately contribute to therapy-related carcinogenesis.

遗传不稳定性是干细胞在再生医学中成功应用的一个主要问题。然而，在人类中应用最广泛的干细胞疗法——造血干细胞移植 (HSCT) 的突变后果仍然未知。在这里，我们使用全基因组测序表征了人类 HSCT 接受者及其供体的造血干细胞和祖细胞 (HSPC) 的突变负担。我们证明大多数移植的 HSPCs 没有显示出改变的突变积累。然而，在一些 HSCT 受者中，我们发现了多个移植后突变负担增加的 HSPC。这种增加可归因于抗病毒药物更昔洛韦引起的独特突变特征。使用机器学习方法，我们在生命早期接受 HSCT 或实体器官移植的个体的癌症基因组中检测到了这种特征。用核苷类似物进行抗病毒治疗可导致移植受者的致突变性增强，这可能最终导致与治疗相关的致癌作用。