Patterson, S.D. , Massett, M., Huang, X. , Jørgensen, H.G. and Michie, A.M. (2024) The MYC–NFATC2 axis maintains the cell cycle and mitochondrial function in acute myeloid leukaemia cells. Molecular Oncology, (doi: 10.1002/1878-0261.13630) (PMID:38459421) (Early Online Publication)
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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.
| Item Type: | Articles |
|---|---|
| Additional Information: | We would like to thank the Wellcome Trust [105614/Z/14/Z], the MRC CiC [18048], the Howat Foundation and Friends of the Paul O’Gorman Leukaemia Research Centre, and the Carnegie Trust [PHD007721] for funding this project. |
| Keywords: | NFATC2, AML, metabolic function, CCND1. |
| Status: | Early Online Publication |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Jorgensen, Dr Heather and Massett, Mr Matthew and Michie, Professor Alison and Patterson, Mr Shaun and Huang, Dr Xu |
| Authors: | Patterson, S.D., Massett, M., Huang, X., Jørgensen, H.G., and Michie, A.M. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Molecular Oncology |
| Publisher: | Wiley |
| ISSN: | 1574-7891 |
| ISSN (Online): | 1878-0261 |
| Published Online: | 08 March 2024 |
| Copyright Holders: | Copyright © 2024 The Authors |
| First Published: | First published in Molecular Oncology 2024 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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