MYC-NFATC2 axis maintains cell cycle and mitochondrial function in AML cells

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 NFATC2 is 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 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-seq and 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 novel 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/567209v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@10b4dc5org.highwire.dtl.DTLVardef@11ed9aaorg.highwire.dtl.DTLVardef@6457a9org.highwire.dtl.DTLVardef@1b722b4_HPS_FORMAT_FIGEXP M_FIG C_FIG Acute myeloid leukaemia (AML) cells of diverse cytogenetic backgrounds are dependent on NFATC2 for survival; in THP-1 cells, NFATC2 is downstream of the epigenetic regulator KDM4A. NFATC2 promotes G1/S phase transition in the cell cycle and oxidative phosphorylation. In addition, NFATC2 functions downstream of transcription factor MYC, and maintains CCND1 expression.