Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1726-1739.e6 |
| Journal | Cell Stem Cell |
| Volume | 28 |
| Issue number | 10 |
| Early online date | 7 Sept 2021 |
| DOIs | |
| Publication status | Published - 7 Oct 2021 |
Bibliographical note
Funding Information:The authors would like to thank the Hartwig Medical Foundation (Amsterdam, the Netherlands) for facilitating low-input whole-genome sequencing scripts. We thank Prof. Holmfeldt, Prof. DiPersio, Dr. Christopher, and Dr. Lolkema for sharing additional clinical data and Jan J. Molenaar and M.L. van den Boogaard for providing the knockout data of OGG1. We are grateful for the insightful counsel of Prof. Dr. Hans Clevers. We thank the Central Biobank of the UMC Utrecht for providing umbilical cord blood samples. Finally, we thank all HSCT recipients and their donors for participation in this study. This study was financially supported by a VIDI grant of the Netherlands Organization for Scientific Research (NWO) ( 016.Vidi.171.023 to R.v.B.), a consolidator grant from the European Research Council (ERC) ( 864499 to R.v.B.), a John Hansen research grant from the DKMS , and a European Society for Blood and Marrow Transplantation Leukemia Fellowship Grant (to M.E.B.).
Funding Information:
The authors would like to thank the Hartwig Medical Foundation (Amsterdam, the Netherlands) for facilitating low-input whole-genome sequencing scripts. We thank Prof. Holmfeldt, Prof. DiPersio, Dr. Christopher, and Dr. Lolkema for sharing additional clinical data and Jan J. Molenaar and M.L. van den Boogaard for providing the knockout data of OGG1. We are grateful for the insightful counsel of Prof. Dr. Hans Clevers. We thank the Central Biobank of the UMC Utrecht for providing umbilical cord blood samples. Finally, we thank all HSCT recipients and their donors for participation in this study. This study was financially supported by a VIDI grant of the Netherlands Organization for Scientific Research (NWO) (016.Vidi.171.023 to R.v.B.), a consolidator grant from the European Research Council (ERC) (864499 to R.v.B.), a John Hansen research grant from the DKMS, and a European Society for Blood and Marrow Transplantation Leukemia Fellowship Grant (to M.E.B.). Conceptualization, M.E.B. and R.v.B.; methodology, M.E.B. and R.v.B.; software, J.K.d.K. F.M. M.J.v.R. R.O. and R.v.B.; formal analysis, J.K.d.K. M.E.B. M.J.v.R. R.O. and R.v.B.; investigation, A.M.B. A.R.H. E.B. M.E.B. F.P. and A.v.L; writing ? original draft, M.E.B. J.K.d.K. and R.v.B.; supervision, M.B. and R.v.B; funding acquisition, M.E.B. and R.v.B. A.R.H. A.v.L. and R.v.B. are named as inventors on a patent application filed resulting from this work.
Publisher Copyright:
© 2021 The Author(s)
