RUNX-mediated growth arrest and senescence are attenuated by diverse mechanisms in cells expressing RUNX1 fusion oncoproteins

Anderson, G. et al. (2018) RUNX-mediated growth arrest and senescence are attenuated by diverse mechanisms in cells expressing RUNX1 fusion oncoproteins. Journal of Cellular Biochemistry, 119(3), pp. 2750-2762. (doi: 10.1002/jcb.26443) (PMID:29052866) (PMCID:PMC5813226)

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Abstract

RUNX gene over-expression inhibits growth of primary cells but transforms cells with tumor suppressor defects, consistent with reported associations with tumor progression. In contrast, chromosomal translocations involving RUNX1 are detectable in utero, suggesting an initiating role in leukemias. How do cells expressing RUNX1 fusion oncoproteins evade RUNX-mediated growth suppression? Previous studies showed that the TEL-RUNX1 fusion from t(12;21) B-ALLs is unable to induce senescence-like growth arrest (SLGA) in primary fibroblasts while potent activity is displayed by the RUNX1-ETO fusion found in t(8;21) AMLs. We now show that SLGA potential is suppressed in TEL-RUNX1 but reactivated by deletion of the TEL HLH domain or mutation of a key residue (K99R). Attenuation of SLGA activity is also a feature of RUNX1-ETO9a, a minor product of t(8;21) translocations with increased leukemogenicity. Finally, while RUNX1-ETO induces SLGA it also drives a potent senescence-associated secretory phenotype (SASP), and promotes the immortalisation of rare cells that escape SLGA. Moreover, the RUNX1-ETO SASP is not strictly linked to growth arrest as it is largely suppressed by RUNX1 and partially activated by RUNX1-ETO9a. These findings underline the heterogeneous nature of premature senescence and the multiple mechanisms by which this failsafe process is subverted in cells expressing RUNX1 oncoproteins.

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 Hay, Dr Jodie and Gilroy, Dr Kathryn and Anderson, Ms Gail
Authors: Anderson, G., Mackay, N., Gilroy, K., Hay, J., Borland, G., McDonald, A., Bell, M., Hassanudin, S. A., Cameron, E., Neil, J. C., and Kilbey, A.
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 Veterinary Medicine
Journal Name:Journal of Cellular Biochemistry
Publisher:Wiley
ISSN:0730-2312
ISSN (Online):1097-4644
Published Online:20 October 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Journal of Cellular Biochemistry 119(3): 2750-2762
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 (CRUK)11951MVLS III - CENTRE FOR VIRUS RESEARCH
539394New Approaches to Modelling Human LeukaemiaEwan CameronBloodwise (BLOODWIS)13046VET - PATHOLOGY, PUBLIC H & DISEASE INV