Acute myeloid leukaemia (AML) is a clonal haematological malignancy affecting the myeloid lineage, with generally poor patient outcomes owing to the lack of targeted therapies. The histone lysine demethylase 4A (KDM4A) has been established as a novel therapeutic target in AML, due to its selective oncogenic role within leukaemic cells. We identify that the transcription factor nuclear factor of activated T cells 2 (NFATC2) is a novel binding and transcriptional target of KDM4A in the human AML THP‐1 cell line. Furthermore, cytogenetically diverse AML cell lines, including THP‐1, were dependent on NFATC2 for colony formation in vitro, highlighting a putative novel mechanism of AML oncogenesis. Our study demonstrates that NFATC2 maintenance of cell cycle progression in human AML cells was driven primarily by CCND1. Through RNA sequencing (RNA‐seq) and chromatin immunoprecipitation sequencing (ChIP‐seq), NFATc2 was shown to bind to the promoter region of genes involved in oxidative phosphorylation and subsequently regulate their gene expression in THP‐1 cells. Furthermore, our data show that NFATC2 shares transcriptional targets with the transcription factor c‐MYC, with MYC knockdown phenocopying NFATC2 knockdown. These data suggest a newly identified co‐ordinated role for NFATC2 and MYC in the maintenance of THP‐1 cell function, indicative of a potential means of therapeutic targeting in human AML.

中文翻译：

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MYC-NFATC2 轴维持急性髓系白血病细胞的细胞周期和线粒体功能

急性髓系白血病（AML）是一种影响骨髓谱系的克隆性血液恶性肿瘤，由于缺乏靶向治疗，患者预后普遍较差。组蛋白赖氨酸去甲基酶 4A (KDM4A) 由于其在白血病细胞中的选择性致癌作用，已被确定为 AML 的新型治疗靶点。我们鉴定出活化 T 细胞的转录因子核因子 2 (NFATC2）是人 AML THP-1 细胞系中 KDM4A 的新型结合和转录靶点。此外，细胞遗传学多样化的 AML 细胞系，包括 THP-1，依赖于NFATC2用于集落形成体外，强调了 AML 肿瘤发生的一种假定的新机制。我们的研究表明NFATC2人类 AML 细胞中细胞周期进程的维持主要由CCND1。通过RNA测序（RNA-seq）和染色质免疫沉淀测序（ChIP-seq），NFATc2被证明与参与氧化磷酸化的基因的启动子区域结合，随后调节它们在THP-1细胞中的基因表达。此外，我们的数据表明NFATC2与转录因子 c-MYC 共享转录目标，我的C敲除表型复制NFATC2击倒。这些数据表明新确定的协调作用NFATC2和我的C维持 THP-1 细胞功能，表明人类 AML 治疗靶向的潜在手段。