Survival differences and associated molecular signatures of DNMT3A-mutant acute myeloid leukemia patients
Survival differences and associated molecular signatures of DNMT3A-mutant acute myeloid leukemia patients
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DOI：
10.1038/s41598-020-69691-8
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发表时间：
2020-07-29
影响因子：
4.6
通讯作者：
Seifert, Michael
中科院分区：
文献类型：
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作者：
Lauber, Chris;Correia, Nadia;Seifert, Michael
急性髓细胞白血病（AML）是一种异质性很强的高度恶性血液肿瘤。DNA甲基转移酶DNMT 3A的突变是AML中最常见的复发性遗传病变之一。大多数DNMT 3A突变型AML患者表现出快速复发和较差的生存率，但也有患者报告了长期生存或长期缓解。导致这些生存差异的潜在分子特征和机制知之甚少，迄今为止尚未详细研究。我们对来自癌症基因组图谱（TCGA）AML队列的51例DNMT 3A突变患者的体细胞基因突变谱进行了分层聚类，揭示了两个在生存率方面存在显著差异的稳健患者亚组。我们进一步确定了区分这两个亚组的分子特征。我们的研究结果表明，FLT 3和/或NPM 1突变有助于DNMT 3A突变患者的生存差异。我们观察到，与长寿患者相比，短寿命患者中p53、VEGF和DNA复制途径的基因上调，PI 3 K-Akt途径的基因下调。我们发现，大多数测量的miRNA在短寿命组中下调，并且我们发现了两个亚组之间差异表达的microRNA，这些microRNA迄今为止尚未在AML中报道（miR-153-2，miR-3065，miR-95，miR-6718），这表明miRNA可能对预后很重要。此外，我们学习了基因调控网络来预测潜在的主要调控因子，并发现了几个在AML发病机制中具有已知作用的基因和miRNA，而且还发现了参与造血、细胞周期、细胞分化和免疫调节的有趣的新候选者，这些候选者可能有助于观察到的两个亚组的生存差异，因此对预后很重要。此外，区分短寿患者和长寿患者的特征性基因突变和表达特征也可预测来自其他队列的独立DNMT 3A突变AML患者，并且还可有助于进一步改善欧洲白血病网（ELN）预后评分系统。我们的研究代表了第一个深入的计算方法，以确定与DNMT 3A突变型AML患者生存差异相关的分子因素，并可能引发其他研究，以开发强大的分子标记物，以便更好地对DNMT 3A突变型AML患者进行分层。
Acute myeloid leukemia (AML) is a very heterogeneous and highly malignant blood cancer. Mutations of the DNA methyltransferase DNMT3A are among the most frequent recurrent genetic lesions in AML. The majority of DNMT3A-mutant AML patients shows fast relapse and poor survival, but also patients with long survival or long-term remission have been reported. Underlying molecular signatures and mechanisms that contribute to these survival differences are only poorly understood and have not been studied in detail so far. We applied hierarchical clustering to somatic gene mutation profiles of 51 DNMT3A-mutant patients from The Cancer Genome Atlas (TCGA) AML cohort revealing two robust patient subgroups with profound differences in survival. We further determined molecular signatures that distinguish both subgroups. Our results suggest that FLT3 and/or NPM1 mutations contribute to survival differences of DNMT3A-mutant patients. We observed an upregulation of genes of the p53, VEGF and DNA replication pathway and a downregulation of genes of the PI3K-Akt pathway in short- compared to long-lived patients. We identified that the majority of measured miRNAs was downregulated in the short-lived group and we found differentially expressed microRNAs between both subgroups that have not been reported for AML so far (miR-153-2, miR-3065, miR-95, miR-6718) suggesting that miRNAs could be important for prognosis. In addition, we learned gene regulatory networks to predict potential major regulators and found several genes and miRNAs with known roles in AML pathogenesis, but also interesting novel candidates involved in the regulation of hematopoiesis, cell cycle, cell differentiation, and immunity that may contribute to the observed survival differences of both subgroups and could therefore be important for prognosis. Moreover, the characteristic gene mutation and expression signatures that distinguished short- from long-lived patients were also predictive for independent DNMT3A-mutant AML patients from other cohorts and could also contribute to further improve the European LeukemiaNet (ELN) prognostic scoring system. Our study represents the first in-depth computational approach to identify molecular factors associated with survival differences of DNMT3A-mutant AML patients and could trigger additional studies to develop robust molecular markers for a better stratification of AML patients with DNMT3A mutations.