The MYC–NFATC2 axis maintains the cell cycle and mitochondrial function in acute myeloid leukaemia cells

Abstract

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.