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

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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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
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
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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172121Funding SchemesAnna DominiczakWellcome Trust (WELLCOTR)105614/Z/14/ZSchool of Cardiovascular & Metabolic Health
306054Confidence in Concept 2019Anna DominiczakMedical Research Council (MRC)MC_PC_18048MVLS - College Senior Management