The discrete roles of individual FOXO transcription factor family members in B-cell malignancies

Lees, J., Hay, J. , Moles, M. W. and Michie, A. M. (2023) The discrete roles of individual FOXO transcription factor family members in B-cell malignancies. Frontiers in Immunology, 14, 1179101. (doi: 10.3389/fimmu.2023.1179101) (PMID:37275916) (PMCID:PMC10233034)

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Forkhead box (FOX) class O (FOXO) proteins are a dynamic family of transcription factors composed of four family members: FOXO1, FOXO3, FOXO4 and FOXO6. As context-dependent transcriptional activators and repressors, the FOXO family regulates diverse cellular processes including cell cycle arrest, apoptosis, metabolism, longevity and cell fate determination. A central pathway responsible for negative regulation of FOXO activity is the phosphatidylinositol-3-kinase (PI3K)-AKT signalling pathway, enabling cell survival and proliferation. FOXO family members can be further regulated by distinct kinases, both positively (e.g., JNK, AMPK) and negatively (e.g., ERK-MAPK, CDK2), with additional post-translational modifications further impacting on FOXO activity. Evidence has suggested that FOXOs behave as ‘bona fide’ tumour suppressors, through transcriptional programmes regulating several cellular behaviours including cell cycle arrest and apoptosis. However, an alternative paradigm has emerged which indicates that FOXOs operate as mediators of cellular homeostasis and/or resistance in both ‘normal’ and pathophysiological scenarios. Distinct FOXO family members fulfil discrete roles during normal B cell maturation and function, and it is now clear that FOXOs are aberrantly expressed and mutated in discrete B-cell malignancies. While active FOXO function is generally associated with disease suppression in chronic lymphocytic leukemia for example, FOXO expression is associated with disease progression in diffuse large B cell lymphoma, an observation also seen in other cancers. The opposing functions of the FOXO family drives the debate about the circumstances in which FOXOs favour or hinder disease progression, and whether targeting FOXO-mediated processes would be effective in the treatment of B-cell malignancies. Here, we discuss the disparate roles of FOXO family members in B lineage cells, the regulatory events that influence FOXO function focusing mainly on post-translational modifications, and consider the potential for future development of therapies that target FOXO activity.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Hay, Dr Jodie and Michie, Professor Alison and Moles, Mr Michael and Lees, Mr Jamie
Authors: Lees, J., Hay, J., Moles, M. W., and Michie, A. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Frontiers in Immunology
Publisher:Frontiers Media
ISSN (Online):1664-3224
Copyright Holders:Copyright © 2023 Lees, Hay, Moles and Michie
First Published:First published in Frontiers in Immunology 14: 1179101
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
303091Elucidating the mechanisms that regulate FOXO activity in chronic lymphocytic leukaemia - a novel target for therapeutic exploitation?Alison MichieBloodwise (BLOODWIS)18003CS - Paul O'Gorman Leukaemia Research Centre