Abstract
INTRODUCTION: Hematopoietic stem cell transplantation is a potentially curative intervention for a broad range of diseases. However, there is evidence that malignant or pre-malignant clones contained in the transplant can expand in the recipient and trigger donor-derived malignancies. This observation has gained much attention in the context of clonal hematopoiesis, a medical condition where significant amounts of healthy blood cells are derived from a small number of hematopoietic stem cell clones. In many cases the dominating clones carry mutations conferring a growth advantage and thus could undergo malignant transformation in the recipient. Since clonal hematopoiesis exists in a significant proportion of potential stem cell donors, a more detailed understanding of its role for stem cell transplantation is required. METHODS: We propose mechanistic computational models and perform virtual clinical trials to investigate clonal dynamics during and after allogenic hematopoietic stem cell transplantation. Different mechanisms of clonal expansion are considered, including mutation-related changes of stem cell proliferation and self-renewal, aberrant response of mutated cells to systemic signals, and self-sustaining chronic inflammation triggered by the mutated cells. RESULTS: Model simulations suggest that an aberrant response of mutated cells to systemic signals is sufficient to explain the frequently observed quick expansion of the mutated clone shortly after transplantation which is followed by a stabilization of the mutated cell number at a constant value. In contrary, a mutation-related increase of self-renewal or self-sustaining chronic inflammation lead to ongoing clonal expansion. Our virtual clinical trials suggest that a low number of transplanted stem cells per kg of body weight increases the transplantation-related expansion of donor-derived clones, whereas the transplanted progenitor dose or growth factor support after transplantation have no impact on clonal dynamics. Furthermore, in our simulations the change of the donors' variant allele frequencies in the year before stem cell donation is associated with the expansion of donor-derived clones in the recipient. DISCUSSION: This in silico study provides insights in the mechanisms leading to clonal expansion and identifies questions that could be addressed in future clinical trials.