MYC–NFATC2 axismaintains cell cycle and mitochondrial function in AML cells

Abstract

AbstractAcute 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 factorNFATC2is a novel binding and transcriptional target of KDM4A in the human AML THP-1 cell line. Further, cytogenetically diverse AML cell lines, including THP-1, were dependent onNFATC2for colony formationin vitro, highlighting a putative novel mechanism of AML oncogenesis.Our study demonstrates thatNFATC2maintenance of cell cycle progression in human AML cells was driven primarily byCCND1. Through RNA-seq and ChIP-seq,NFATC2was 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 thatNFATC2shares transcriptional targets with the transcription factor c-MYC, withMYCknockdown phenocopyingNFATC2knockdown. These data suggest a novel co-ordinated role forNFATC2andMYCin the maintenance of THP-1 cell function, indicative of a potential means of therapeutic targeting in human AML.Graphical AbstractAcute myeloid leukaemia (AML) cells of diverse cytogenetic backgrounds are dependent onNFATC2for survival; in THP-1 cells,NFATC2is downstream of the epigenetic regulatorKDM4A.NFATC2promotes G1/S phase transition in the cell cycle and oxidative phosphorylation. In addition,NFATC2functions downstream of transcription factorMYC, and maintainsCCND1expression.