Genetic mutations in acute myeloid leukaemia (AML) are assumed to occur in a sequential order; however, the predominant hierarchical roles of specific mutated genes have not been fully described. In this study, we aimed to determine the clonal involvement of the most frequent AML‐associated mutations. Using a targeted sequencing panel for 18 genes, we traced changes and relative clonal contribution of mutations in 52 patients. We analysed 35 pairs of diagnosis and relapse samples, 27 pairs of primary samples and corresponding patient‐derived xenografts, and 34 pairs of total leukocytes and corresponding isolated primitive cells or blast populations. In both relapse and xenografts, we observed conservation of main leukaemic clones and variability was limited to subclones with late‐acquired mutations. AML evolution thus mainly involved modification of subclones while the clonal background remained unchanged. NPM1 mutations were identified as the most probable leukaemia‐transformation lesion, remaining conserved in contrast to high variation of accompanying subclonal FLT3 and NRAS mutations. DNMT3A mutations represented the most stable mutations forming a preleukaemic background in most samples. Mutations in genes IDH1/2, TET2, RUNX1, ASXL1 and U2AF1 were detected both as preleukaemic and as subclonal lesions, suggesting a non‐specific order of acquisition.

中文翻译：

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急性髓细胞性白血病主要分子病变的克隆层次。

假定急性髓细胞性白血病（AML）的基因突变是按顺序发生的。然而，尚未完全描述特定突变基因的主要等级作用。在这项研究中，我们旨在确定最常见的AML相关突变的克隆参与程度。使用针对18个基因的靶向测序小组，我们追踪了52位患者的突变变化和相对克隆贡献。我们分析了35对诊断和复发样本，27对主要样本和相应的患者来源的异种移植物以及34对总白细胞和相应的分离的原始细胞或原始细胞群体。在复发和异种移植中，我们都观察到了主要的白血病克隆的保守性，并且变异仅限于具有较晚获得的突变的亚克隆。NPM1突变被确定为最可能的白血病转化病灶，与伴随的亚克隆FLT3和NRAS突变的高变异相比，它仍然是保守的。在大多数样品中，DNMT3A突变代表最稳定的突变，形成白血病前背景。IDH1 / 2，TET2，RUNX1，ASXL1和U2AF1基因的突变均被检出为白血病前期和亚克隆病灶，提示其获取的顺序不明确。