ETS-related gene (ERG) amplification, observed in 4–6% of acute myeloid leukemia (AML), is associated with unfavorable prognosis. To determine coincident effects of additional genomic abnormalities in AML with ERG amplification (ERGamp), we examined 11 ERGamp cases of 205 newly diagnosed AML using chromosomal microarray analysis and next generation sequencing. ERGamp cases demonstrated a distinct pattern of high genetic complexity: loss of 5q, chromothripsis and TP53 loss of function variants. Remarkably, allelic TP53 loss or loss of heterozygosity (LOH) co-occurring with TP53 inactivating mutation dramatically effected ERGamp tumor patient outcome. In the presence of homozygous TP53 loss of function, ERGamp patients demonstrated no response to induction chemotherapy with median overall survival (OS) of 3.8 months (N = 9). Two patients with heterozygous loss of TP53 function underwent alloSCT without evidence of relapse at one year. Similarly, a validation TCGA cohort, 6 of the 8 ERGamp cases with TP53 loss of function demonstrated median OS of 2.5 months. This suggests that with TP53 mutant ERGamp AML, successive loss of the second TP53 allele, typically by 17p deletion or LOH identifies a specific high-risk subtype of AML patients who are resistant to standard induction chemotherapy and need novel approaches to avert the very poor prognosis.

在 4-6% 的急性髓性白血病 (AML) 中观察到的ETS 相关基因 ( ERG ) 扩增与不良预后相关。为了确定 AML 中其他基因组异常与ERG扩增（ERG放大器）的重合效应，我们使用染色体微阵列分析和下一代测序检查了 205 名新诊断的 AML 中的11 例ERG放大器病例。ERG amp 病例表现出高遗传复杂性的独特模式：5q 缺失、染色体碎裂和 TP53 功能缺失变异。值得注意的是，等位基因 TP53 丢失或杂合性丢失 (LOH) 与 TP53 失活突变同时发生显着影响ERG放大器肿瘤患者的结果。在存在纯合子 TP53 功能丧失的情况下，ERG amp 患者对诱导化疗没有反应，中位总生存期 (OS) 为 3.8 个月 ( N  = 9)。两名 TP53 功能缺失的杂合子患者接受了同种异体干细胞移植，一年后没有复发迹象。同样，在验证 TCGA 队列中，8 个TP53 功能丧失的ERG amp 病例中有 6 个显示中位 OS 为 2.5 个月。这表明，对于 TP53 突变体ERG和 AML，第二个 TP53 等位基因的连续丢失（通常是 17p 缺失或 LOH）确定了 AML 患者的特定高风险亚型，这些患者对标准诱导化疗有抵抗力，需要新的方法来避免非常贫穷的人预后。