Addiction to Runx1 is partially attenuated by loss of p53 in the Eμ-Myc lymphoma model

Borland, G. et al. (2016) Addiction to Runx1 is partially attenuated by loss of p53 in the Eμ-Myc lymphoma model. Oncotarget, 7(17), pp. 22973-22987. (doi: 10.18632/oncotarget.8554) (PMID:27056890) (PMCID:PMC5029604)

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Abstract

The Runx genes function as dominant oncogenes that collaborate potently with Myc or loss of p53 to induce lymphoma when over-expressed. Here we examined the requirement for basal Runx1 activity for tumor maintenance in the Eµ-Myc model of Burkitt’s lymphoma. While normal Runx1fl/fl lymphoid cells permit mono-allelic deletion, primary Eµ-Myc lymphomas showed selection for retention of both alleles and attempts to enforce deletion in vivo led to compensatory expansion of p53null blasts retaining Runx1. Surprisingly, Runx1 could be excised completely from established Eµ- Myc lymphoma cell lines in vitro without obvious effects on cell phenotype. Established lines lacked functional p53, and were sensitive to death induced by introduction of a temperature-sensitive p53 (Val135) allele. Transcriptome analysis of Runx1-deleted cells revealed a gene signature associated with lymphoid proliferation, survival and differentiation, and included strong de-repression of recombination-activating (Rag) genes, an observation that was mirrored in a panel of human acute leukemias where RUNX1 and RAG1,2 mRNA expression were negatively correlated. Notably, despite their continued growth and tumorigenic potential, Runx1null lymphoma cells displayed impaired proliferation and markedly increased sensitivity to DNA damage and dexamethasone-induced apoptosis, validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cameron, Professor Ewan and Neil, Professor James and Mcdonald, Mrs Alma and Bell, Mrs Margaret and Kilbey, Dr Anna and Borland, Dr Gillian and Gilroy, Dr Kathryn and Hay, Dr Jodie and Terry, Mrs Anne
Authors: Borland, G., Kilbey, A., Hay, J., Gilroy, K., Terry, A., Mackay, N., Bell, M., Mcdonald, A., Mills, K., Cameron, E., 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:Oncotarget
Publisher:Impact Journals
ISSN:1949-2553
Published Online:02 April 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Oncotarget 7(17):22973-22987
Publisher Policy:Reproduced under a Creative Commons License

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