The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure1. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion2,3. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)4–8. Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.Individuals who are at high risk of developing acute myeloid leukaemia can be identified years before diagnosis using genetic information from blood samples.

中文翻译：

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健康个体急性髓性白血病风险的预测

急性髓性白血病 (AML) 的发病率随着年龄的增长而增加，在 65 岁后确诊时死亡率超过 90%。大多数病例出现时没有任何可检测的早期症状，患者通常出现骨髓衰竭的急性并发症1。这种新发 AML 病例的发病通常先于经历克隆扩增的白血病前期造血干细胞和祖细胞 (HSPC) 中体细胞突变的积累2, 3。然而，在没有发展为 AML 的健康个体的衰老过程中，复发性 AML 突变也会在 HSPC 中积累，这种现象被称为与年龄相关的克隆性造血 (ARCH)4-8。在这里，我们使用深度测序来分析在 AML 中反复突变的基因，以区分具有发生 AML 高风险的个体和具有良性 ARCH 的个体。我们分析了 AML 诊断前平均 6.3 年获得的 95 名个体的外周血细胞（AML 前组），以及 414 名未选择的年龄和性别匹配的个体（对照组）。前 AML 病例与对照不同，每个样本的突变更多，变异等位基因频率更高，表明克隆扩增更大，并显示特定基因突变富集。遗传参数用于推导出准确预测无 AML 生存的模型；该模型在 29 例 AML 前病例和 262 例对照的独立队列中得到验证。由于 AML 很少见，我们还使用大型电子健康记录数据库开发了一个 AML 预测模型，该模型可以识别风险更大的个体。总的来说，我们的研究结果提供了概念验证，即有可能在恶性转化之前多年将 ARCH 与 pre-AML 区分开来。这可以在未来实现更早的检测和监测，并可能有助于为干预提供信息。使用血液样本中的遗传信息可以在诊断前数年识别出患急性髓细胞白血病的高风险个体。