Stiehl Thomas
Aachen Medical School, Institute for Computational Biomedicine & Disease Modeling, RWTH Aachen University, Aachen, Germany.
Department for Science and Environment, Roskilde University, Roskilde, Denmark.
Front Immunol. 2024 Dec 16;15:1321336. doi: 10.3389/fimmu.2024.1321336. eCollection 2024.
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.
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.
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.
This in silico study provides insights in the mechanisms leading to clonal expansion and identifies questions that could be addressed in future clinical trials.
造血干细胞移植是一种对多种疾病具有潜在治愈作用的干预措施。然而，有证据表明移植中所含的恶性或癌前克隆可在受者体内扩增并引发供体来源的恶性肿瘤。这一观察结果在克隆性造血的背景下受到了广泛关注，克隆性造血是一种医学状况，其中大量健康血细胞来源于少数造血干细胞克隆。在许多情况下，占主导地位的克隆携带赋予生长优势的突变，因此可能在受者体内发生恶性转化。由于相当比例的潜在干细胞供体中存在克隆性造血，因此需要更详细地了解其在干细胞移植中的作用。
我们提出了机制性计算模型并进行虚拟临床试验，以研究异基因造血干细胞移植期间及之后的克隆动态。考虑了克隆扩增的不同机制，包括与突变相关的干细胞增殖和自我更新变化、突变细胞对全身信号的异常反应以及由突变细胞触发的自我维持性慢性炎症。
模型模拟表明，突变细胞对全身信号的异常反应足以解释移植后不久经常观察到的突变克隆的快速扩增，随后突变细胞数量稳定在恒定值。相反，与突变相关的自我更新增加或自我维持性慢性炎症会导致克隆持续扩增。我们的虚拟临床试验表明，每千克体重移植的干细胞数量较少会增加供体来源克隆的移植相关扩增，而移植后的祖细胞剂量或生长因子支持对克隆动态没有影响。此外，在我们的模拟中，干细胞捐献前一年供体变异等位基因频率的变化与受者体内供体来源克隆的扩增有关。
这项计算机模拟研究提供了对导致克隆扩增机制的见解，并确定了未来临床试验中可以解决的问题。
