Genome-wide identification of FHL1 as a powerful prognostic candidate and potential therapeutic target in acute myeloid leukaemia
Genome-wide identification of FHL1 as a powerful prognostic candidate and potential therapeutic target in acute myeloid leukaemia
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全基因组鉴定 FHL1 作为急性髓系白血病的强大预后候选者和潜在治疗靶点。
DOI：
10.1016/j.ebiom.2020.102664
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发表时间：
2020-02-01
期刊：
影响因子：
11.1
通讯作者：
Chen, Chunyan
中科院分区：
文献类型：
--
作者：
Fu, Yue;Xu, Man;Chen, Chunyan
背景：急性髓系白血病（AML）是一种异质性和死亡率高的恶性血液系统肿瘤。可靠的预后评估对治疗策略至关重要。方法：采用全基因组单因素考克斯回归分析方法，对3个独立的AML数据集进行AML相关基因的筛选。Kaplan-Meier生存分析用于验证FHL 1在评价1298例初治AML患者、648例非急性早幼粒细胞白血病AML患者和407例细胞遗传学正常AML患者的总生存期中的疗效;其中一些患者的数据也用于EFS和RFS验证。进行多变量考克斯回归以验证FHL 1作为独立预后指标。应用WGCNA、GSEA和基因相关性分析等方法探讨FHL 1在AML中的作用机制。在体外实验中验证了FHL 1敲低的协同杀细胞作用。结果：全面的全基因组分析和大样本验证表明，FHL 1是AML患者总生存率、无事件生存率和无复发生存率的强有力的预后候选者，并且独立于肿瘤相关的临床因素和遗传异常。其分子机制可能通过调节白血病干细胞中的FHL 1、肿瘤相关信号通路和化疗药物的跨膜转运而发生。FHL 1靶向干预可增强AML细胞对阿糖胞苷的敏感性解读：FHL 1可作为临床策略选择的评价因素，其靶向干预可能有利于AML患者的化疗。(C)2020年，任作家。由爱思唯尔公司出版
Background: Acute myeloid leukaemia (AML) is a malignant haematological tumour with high heterogeneity and mortality. A reliable prognostic assessment is critical for treatment strategies. However, the current prognostic evaluation system of AML is insufficient.Methods: Genome-wide univariate Cox regression analysis was performed on three independent AML datasets to screen for the prognostic-related genes. Kaplan-Meier survival analysis was employed to verify the efficacy of FHL1 in evaluating overall survival in 1298 de novo AML patients, 648 non-acute promyelocytic leukaemia AML patients and 407 cytogenetically normal AML patients; the data for some of these patients were also used for EFS and RFS validation. Multivariate Cox regression was performed to validate FHL1 as an independent prognostic indicator. WGCNA, GSEA, and gene correlation analysis were applied to explore the mechanism of FHL1 in AML. The synergistic cytocidal effect of FHL1 knockdown was verified in in vitro experiments.Findings: Comprehensive genome-wide analyses and large-sample validation showed that FHL1 is a powerful prognostic candidate for overall survival, event-free survival, and relapse-free survival in AML and is independent of prognosis-related clinical factors and genetic abnormalities. The molecular mechanism may occur through regulation of FHL1 in leukaemia stem cells, tumour-associated signalling pathways, and transmembrane transport of chemotherapeutic drugs. FHL1-targeted intervention enhances the sensitivity of AML cells to cytarabine.Interpretation: FHL1 may serve as an evaluation factor for clinical strategy selection, and its targeted intervention may be beneficial for chemotherapy in AML patients. (C) 2020 The Authors. Published by Elsevier B.V.