Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia.

In acquired aplastic anemia, the immune system destroys hematopoietic cells, leading to pancytopenia. Patients respond to immunosuppressive therapy but about 15 per cent develop myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), usually many months to years after diagnosis. Next generation sequencing and array-based karyotyping were performed using 668 blood samples from 439 aplastic anemia patients; serial samples were analyzed in 82. Somatic mutations in myeloid malignancy candidate genes were present in 1/3 of patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of patients, most frequently as acquired mutations. Mutation prevalence increased with age and mutations had an age-related signature. DNMT3A- and ASXL1-mutated clones tended to increase in size over time; BCOR/BCORL1 and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR/BCORL1 correlated with better response to immunosuppressive therapy and better overall and progression-free survival; mutations in a subset of genes including DNMT3A and ASXL1 associated with worse outcomes. However, complex patterns of clonal dynamics were compatible with improvement after therapy and long survival in individual cases. Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable.

在获得性再生障碍性贫血中，免疫系统破坏造血细胞，导致全血细胞减少。患者对免疫抑制疗法有反应，但约15%的患者会发展为骨髓增生异常综合征（MDS）和急性髓系白血病（AML），通常在确诊后数月至数年发生。 使用来自439例再生障碍性贫血患者的668份血液样本进行了新一代测序和基于阵列的核型分析；对82例患者的系列样本进行了分析。 1/3的患者存在髓系恶性肿瘤候选基因的体细胞突变，涉及的基因数量有限，且初始变异等位基因频率较低。在47%的患者中检测到克隆性造血，最常见的是获得性突变。突变患病率随年龄增长而增加，且突变具有与年龄相关的特征。DNMT3A和ASXL1突变的克隆随时间推移有增大的趋势；BCOR/BCORL1和PIGA突变的克隆减小或保持稳定。PIGA和BCOR/BCORL1突变与对免疫抑制疗法更好的反应以及更好的总生存期和无进展生存期相关；包括DNMT3A和ASXL1在内的一组基因的突变与更差的预后相关。然而，克隆动态的复杂模式与治疗后的改善以及个别病例的长期生存是相符的。 克隆性造血在再生障碍性贫血中普遍存在。一些突变与临床结果相关。一组高度偏向性的突变是在衰竭的骨髓环境中达尔文选择的证据。个体患者随时间推移的体细胞克隆模式是可变的，且常常不可预测。