Acute myelogenous leukemia (AML) frequently relapses after complete remission (CR), necessitating improved detection and phenotypic characterization of treatment-resistant residual disease. In this work, we have optimized droplet digital PCR to broadly measure mutated alleles of recurrently mutated genes in CR marrows of AML patients at levels as low as 0.002% variant allele frequency. Most gene mutations persisted in CR, albeit at highly variable and gene-dependent levels. The majority of AML cases demonstrated residual aberrant oligoclonal hematopoiesis. Importantly, we detected very rare cells (as few as 1 in 15,000) that were genomically similar to the dominant blast populations at diagnosis and were fully clonally represented at relapse, identifying these rare cells as one common source of AML relapse. Clinically, the mutant allele burden was associated with overall survival in AML, and our findings narrow the repertoire of gene mutations useful in minimal residual disease–based prognostication in AML. Overall, this work delineates rare cell populations that cause AML relapse, with direct implications for AML research directions and strategies to improve AML therapies and outcome.

中文翻译：

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超灵敏突变检测可识别导致急性粒细胞性白血病复发的稀有残留细胞

完全缓解（CR）后，急性骨髓性白血病（AML）经常复发，因此有必要改善对耐药性残留疾病的检测和表型特征。在这项工作中，我们优化了液滴数字PCR，以广泛测量AML患者CR骨髓中复发突变基因的突变等位基因，其水平低至0.002％变异等位基因频率。大多数基因突变在CR中仍然存在，尽管处于高度可变且依赖基因的水平。多数AML病例表现出残留的异常寡血造血作用。重要的是，我们检测到非常罕见的细胞（在15,000中少至1个），在基因组上与诊断时的显性母细胞群体在基因组上相似，并且在复发时被完全克隆表示，从而将这些罕见细胞确定为AML复发的一种常见来源。临床上 突变的等位基因负担与AML的整体存活率相关，我们的发现缩小了基因突变的范围，这些基因突变可用于将基于AML的最小残留疾病的预后降至最低。总的来说，这项工作描述了导致AML复发的稀有细胞群，对AML研究方向和改善AML治疗和结果的策略有着直接的影响。