Runx1 orchestrates sphingolipid metabolism and glucocorticoid resistance in lymphomagenesis

Kilbey, A. et al. (2017) Runx1 orchestrates sphingolipid metabolism and glucocorticoid resistance in lymphomagenesis. Journal of Cellular Biochemistry, 118(6), pp. 1432-1441. (doi: 10.1002/jcb.25802) (PMID:27869314) (PMCID:PMC5408393)

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Abstract

The three-membered RUNX gene family includes RUNX1, a major mutational target in human leukemias, and displays hallmarks of both tumour suppressors and oncogenes. In mouse models the Runx genes appear to act as conditional oncogenes, as ectopic expression is growth suppressive in normal cells but drives lymphoma development potently when combined with over-expressed Myc or loss of p53. Clues to underlying mechanisms emerged previously from murine fibroblasts where ectopic expression of any of the Runx genes promotes survival through direct and indirect regulation of key enzymes in sphingolipid metabolism associated with a shift in the ‘sphingolipid rheostat’ from ceramide to sphingosine-1-phosphate (S1P). Testing of this relationship in lymphoma cells was therefore a high priority. We find that ectopic expression of Runx1 in lymphoma cells consistently perturbs the sphingolipid rheostat, while an essential physiological role for Runx1 is revealed by reduced S1P levels in normal spleen after partial Cre-mediated excision. Furthermore we show that ectopic Runx1 expression confers increased resistance of lymphoma cells to glucocorticoid-mediated apoptosis, and elucidate the mechanism of cross-talk between glucocorticoid and sphingolipid metabolism through Sgpp1. Dexamethasone potently induces expression of Sgpp1 in T-lymphoma cells and drives cell death which is reduced by partial knockdown of Sgpp1 with shRNA or direct transcriptional repression of Sgpp1 by ectopic Runx1. Together these data show that Runx1 plays a role in regulating the sphingolipid rheostat in normal development and that perturbation of this cell fate regulator contributes to Runx-driven lymphomagenesis.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Neil, Professor James and Kilbey, Dr Anna and Cameron, Professor Ewan and Terry, Mrs Anne and Borland, Dr Gillian
Authors: Kilbey, A., Terry, A., Wotton, S., Borland, G., Zhang, Q., Mackay, N., McDonald, A., Bell, M., Wakelam, M.J.O., Cameron, E.R., and Neil, J.C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Journal Name:Journal of Cellular Biochemistry
Publisher:Wiley
ISSN:0730-2312
ISSN (Online):1097-4644
Published Online:21 November 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Journal of Cellular Biochemistry 118(6):1432-1441
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
539393New Approaches to Modelling Human LeukaemiaEwan CameronBloodwise (LLR)13046VET - PATHOLOGY, PUBLIC H & DISEASE INV
539151New Approaches to Modelling Human LeukaemiaJames NeilCancer Research UK (CRUK)11951MVLS III - CENTRE FOR VIRUS RESEARCH