Collaboration of MYC and RUNX2 in lymphoma simulates T‐cell receptor signaling and attenuates p53 pathway activity

Hay, J. , Gilroy, K., Huser, C. , Kilbey, A., Mcdonald, A., MacCallum, A., Holroyd, A. , Cameron, E. and Neil, J. C. (2019) Collaboration of MYC and RUNX2 in lymphoma simulates T‐cell receptor signaling and attenuates p53 pathway activity. Journal of Cellular Biochemistry, 120(10), pp. 18332-18345. (doi: 10.1002/jcb.29143) (PMID:31257681) (PMCID:PMC6772115)

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Abstract

MYC and RUNX oncogenes each trigger p53‐mediated failsafe responses when overexpressed in vitro and collaborate with p53 deficiency in vivo. However, together they drive rapid onset lymphoma without mutational loss of p53. This phenomenon was investigated further by transcriptomic analysis of premalignant thymus from RUNX2/MYC transgenic mice. The distinctive contributions of MYC and RUNX to transcriptional control were illustrated by differential enrichment of canonical binding sites and gene ontology analyses. Pathway analysis revealed signatures of MYC, CD3, and CD28 regulation indicative of activation and proliferation, but also strong inhibition of cell death pathways. In silico analysis of discordantly expressed genes revealed Tnfsrf8/CD30, Cish, and Il13 among relevant targets for sustained proliferation and survival. Although TP53 mRNA and protein levels were upregulated, its downstream targets in growth suppression and apoptosis were largely unperturbed. Analysis of genes encoding p53 posttranslational modifiers showed significant upregulation of three genes, Smyd2, Set, and Prmt5. Overexpression of SMYD2 was validated in vivo but the functional analysis was constrained by in vitro loss of p53 in RUNX2/MYC lymphoma cell lines. However, an early role is suggested by the ability of SMYD2 to block senescence‐like growth arrest induced by RUNX overexpression in primary fibroblasts.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Gilroy, Dr Kathryn and Hay, Dr Jodie and Cameron, Professor Ewan and Maccallum, Dr Amanda and Neil, Professor James and Holroyd, Dr Ailsa and Mcdonald, Mrs Alma and Kilbey, Dr Anna and Huser, Dr Camille
Authors: Hay, J., Gilroy, K., Huser, C., Kilbey, A., Mcdonald, A., MacCallum, A., Holroyd, A., Cameron, E., and Neil, J. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
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:30 June 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Journal of Cellular Biochemistry 120(10):18332-18345
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 (BLOODWIS)13046VET - PATHOLOGY, PUBLIC H & DISEASE INV
539151New Approaches to Modelling Human LeukaemiaJames NeilCancer Research UK (CRUK)11951MVLS III - CENTRE FOR VIRUS RESEARCH