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)
|
Text
118035.pdf - Published Version Available under License Creative Commons Attribution. 5MB |
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: | Bell, Mrs Margaret and Cameron, Professor Ewan and Kilbey, Dr Anna and Borland, Dr Gillian and Gilroy, Dr Kathryn and Hay, Dr Jodie and Neil, Professor James and Mcdonald, Mrs Alma 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 > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research |
| 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 |
University Staff: Request a correction | Enlighten Editors: Update this record
Altmetric
Altmetric