Poon Gladys, Vedi Aditi, Sanders Mathijs, Laurenti Elisa, Valk Peter, Blundell Jamie R
Early Cancer Institute, University of Cambridge, Cambridge, UK.
Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Cambridge University Hospital NHS Foundation Trust, Cambridge, UK.
Cell Genom. 2025 Feb 12;5(2):100744. doi: 10.1016/j.xgen.2024.100744. Epub 2025 Jan 21.
The representation of driver mutations in preleukemic hematopoietic stem cells (pHSCs) provides a window into the somatic evolution that precedes acute myeloid leukemia (AML). Here, we isolate pHSCs from the bone marrow of 16 patients diagnosed with AML and perform single-cell DNA sequencing on thousands of cells to reconstruct phylogenetic trees of the major driver clones in each patient. We develop a computational framework that can infer levels of positive selection operating during preleukemic evolution from the statistical properties of these phylogenetic trees. Combining these data with 67 previously published phylogenetic trees, we find that the highly variable structures of preleukemic trees emerge naturally from a simple model of somatic evolution with pervasive positive selection typically in the range of 9%-24% per year. At these levels of positive selection, we show that the identification of early multiple-mutant clones could be used to identify individuals at risk of future AML.
白血病前期造血干细胞（pHSCs）中驱动突变的表现为急性髓系白血病（AML）之前的体细胞进化提供了一个窗口。在此，我们从16名被诊断为AML的患者的骨髓中分离出pHSCs，并对数千个细胞进行单细胞DNA测序，以重建每位患者主要驱动克隆的系统发育树。我们开发了一个计算框架，该框架可以从这些系统发育树的统计特性推断白血病前期进化过程中正向选择的水平。将这些数据与之前发表的67个系统发育树相结合，我们发现白血病前期树的高度可变结构自然地源于一个简单的体细胞进化模型，其中普遍存在正向选择，通常每年在9% - 24%的范围内。在这些正向选择水平下，我们表明识别早期多突变克隆可用于识别未来有患AML风险的个体。
