Clonal dynamics after allogeneic haematopoietic cell transplantation

Michael Spencer Chapman, C. Matthias Wilk, Steffen Boettcher, Emily Mitchell, Kevin Dawson, Nicholas Williams, Jan Müller, Larisa Kovtonyuk, Hyunchul Jung, Francisco Caiado, Kirsty Roberts, Laura O’Neill, David G. Kent, Anthony R. Green, Jyoti Nangalia, Markus G. Manz () and Peter J. Campbell ()
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Michael Spencer Chapman: Wellcome Sanger Institute
C. Matthias Wilk: University of Zurich and University Hospital Zurich
Steffen Boettcher: University of Zurich and University Hospital Zurich
Emily Mitchell: Wellcome Sanger Institute
Kevin Dawson: Wellcome Sanger Institute
Nicholas Williams: Wellcome Sanger Institute
Jan Müller: University of Zurich and University Hospital Zurich
Larisa Kovtonyuk: University of Zurich and University Hospital Zurich
Hyunchul Jung: Wellcome Sanger Institute
Francisco Caiado: University of Zurich and University Hospital Zurich
Kirsty Roberts: Wellcome Sanger Institute
Laura O’Neill: Wellcome Sanger Institute
David G. Kent: Jeffrey Cheah Biomedical Centre
Anthony R. Green: Jeffrey Cheah Biomedical Centre
Jyoti Nangalia: Wellcome Sanger Institute
Markus G. Manz: University of Zurich and University Hospital Zurich
Peter J. Campbell: Wellcome Sanger Institute

Nature, 2024, vol. 635, issue 8040, 926-934

Abstract: Abstract Allogeneic haematopoietic cell transplantation (HCT) replaces the stem cells responsible for blood production with those from a donor1,2. Here, to quantify dynamics of long-term stem cell engraftment, we sequenced genomes from 2,824 single-cell-derived haematopoietic colonies of ten donor–recipient pairs taken 9–31 years after HLA-matched sibling HCT3. With younger donors (18–47 years at transplant), 5,000–30,000 stem cells had engrafted and were still contributing to haematopoiesis at the time of sampling; estimates were tenfold lower with older donors (50–66 years). Engrafted cells made multilineage contributions to myeloid, B lymphoid and T lymphoid populations, although individual clones often showed biases towards one or other mature cell type. Recipients had lower clonal diversity than matched donors, equivalent to around 10–15 years of additional ageing, arising from up to 25-fold greater expansion of stem cell clones. A transplant-related population bottleneck could not explain these differences; instead, phylogenetic trees evinced two distinct modes of HCT-specific selection. In pruning selection, cell divisions underpinning recipient-enriched clonal expansions had occurred in the donor, preceding transplant—their selective advantage derived from preferential mobilization, collection, survival ex vivo or initial homing. In growth selection, cell divisions underpinning clonal expansion occurred in the recipient’s marrow after engraftment, most pronounced in clones with multiple driver mutations. Uprooting stem cells from their native environment and transplanting them to foreign soil exaggerates selective pressures, distorting and accelerating the loss of clonal diversity compared to the unperturbed haematopoiesis of donors.

Date: 2024
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DOI: 10.1038/s41586-024-08128-y

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