Abstract：
Pediatric acute myeloid leukemia (AML) is a poor prognostic subtype of pediatric leukemia. However, the detailed characteristics of many genetic abnormalities are yet to be established in this disease. Although TP53 and RB1 are established as representative tumor suppressor genes in various cancers, alterations of these two genes, especially RB1, have not been characterized in pediatric AML. We performed next-generation sequencing in 328 pediatric AML patients from the Japanese AML-05 trial to ascertain TP53 and RB1 alterations, and their prognostic implications. We identified seven patients with TP53 alterations (2.1%) and six patients with RB1 alterations (1.8%). These alterations were found in only patients without RUNX1::RUNX1T1, CBFB::MYH11, or KMT2A rearrangements. TP53 and RB1 were frequently co-deleted with their neighboring genes PRPF8 and ELF1, respectively. Patients with TP53 alterations had significantly lower 5-year overall survival (OS; 14.3% vs. 71.4%, p < 0.001) and lower 5-year event-free survival (EFS; 0% vs. 56.3%, p < 0.001); similarly, patients with RB1 had significantly lower 5-year OS (0% vs. 71.8%, p < 0.001) and lower 5-year EFS (0% vs. 56.0%, p < 0.001) when compared to patients without these alterations. In gene expression analyses, oxidative phosphorylation, glycolysis, and protein secretion were upregulated in patients with TP53 and/or RB1 alterations. Additionally, Kaplan-Meier analysis revealed that high expressions of SLC2A5, KCNAB2, and CD300LF were related to poor OS of non-core-binding factor AML patients (p < 0.001, p = 0.001, and p = 0.021, respectively). This study will contribute to the development of risk-stratified therapy and precision medicine in pediatric AML.
摘要：
小儿急性髓性白血病（AML）是小儿白血病的预后不良亚型。然而,在这种疾病中，许多遗传异常的详细特征尚未确定。尽管TP53和RB1在各种癌症中被确立为代表性的抑癌基因，这两个基因的改变，尤其是RB1，尚未在小儿AML中表征。我们在日本AML-05试验的328名儿科AML患者中进行了下一代测序，以确定TP53和RB1改变。以及它们对预后的影响。我们确定了7例TP53改变的患者（2.1％）和6例RB1改变的患者（1.8％）。这些改变仅在没有RUNX1::RUNX1T1、CBFB::MYH11或KMT2A重排的患者中发现。TP53和RB1通常分别与它们的邻近基因PRPF8和ELF1共同缺失。TP53改变的患者的5年总生存率显着降低（OS；14.3％vs.71.4%,p<0.001）和较低的5年无事件生存率（EFS；0%vs.56.3%,p<0.001)；类似地，RB1患者的5年OS显着降低（0％vs.71.8%,p<0.001)和较低的5年期EFS(0%与56.0%,与没有这些改变的患者相比，p<0.001)。在基因表达分析中，氧化磷酸化，糖酵解,TP53和/或RB1改变患者的蛋白质分泌上调。此外,Kaplan-Meier分析显示，SLC2A5，KCNAB2和CD300LF的高表达与非核心结合因子AML患者的OS差相关（分别为p<0.001，p=0.001和p=0.021）。这项研究将有助于儿童AML风险分层治疗和精准医学的发展。
