NPM1 mutation-modulated microRNA−mRNA regulation in acute myeloid leukemia [miRNA]. Homo sapiens

Mutation in the nucleophosmin (NPM1) gene is frequent in acute myeloid leukemia (AML). This mutation has remarkable prognostic significance and correlates with distinct biological features. Our data from the sample-paired microRNA (miRNA) and mRNA microarrays of de novo AML patients strongly indicated that miRNA−mRNA regulation (MMR) may be dynamic and can be modulated by NPM1 mutation. We identified 493 NPM1 mutation-modulated MMR pairs by a systematic framework, in which MMR was attenuated specifically in patients carrying NPM1 mutations. The involved miRNAs/mRNAs were associated with cancer and hematological diseases, as well as known functions of NPM1 mutation including cell death and cellular response to therapeutics. The NPM1 mutation modulation could be validated with three approaches, including two independent cohort datasets, a high-throughput dataset derived from cell line-based experiments, and two in vitro models. Our study provides novel biological insights into the role of NPM1 mutation as a modulator of MMR, based on which novel prognostic markers are derived in AML. Overall design: Cryopreserved bone marrow cells were obtained from 109 de novo AML patients. Each sample was analyzed with nCounter® Human miRNA Expression Array.

核仁磷酸蛋白（nucleophosmin, NPM1）基因的突变在急性髓系白血病（acute myeloid leukemia, AML）中较为常见。该突变具有显著的预后价值，且与独特的生物学特征密切相关。本研究针对109例初诊急性髓系白血病患者的样本配对微小RNA（microRNA, miRNA）与信使RNA（messenger RNA, mRNA）芯片数据进行分析，结果强烈提示miRNA-mRNA调控（miRNA−mRNA regulation, MMR）具有动态性，且可受NPM1突变调控。我们通过系统性分析框架，共鉴定出493个受NPM1突变调控的MMR对，且此类调控在携带NPM1突变的患者中呈现特异性减弱。所涉及的miRNA/mRNA分子与肿瘤、血液系统疾病，以及NPM1突变已知的相关功能（如细胞死亡、细胞对治疗的应答）密切相关。NPM1突变对MMR的调控作用可通过三种方法验证：包括两组独立的队列数据集、一套基于细胞系实验的高通量数据集，以及两套体外模型。本研究为NPM1突变作为MMR调控因子的作用机制提供了全新的生物学见解，并基于此鉴定出急性髓系白血病中新的预后标志物。实验设计：本研究从109例初诊急性髓系白血病患者中获取冻存骨髓细胞，每份样本均通过nCounter®人类微小RNA表达芯片完成检测分析。