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Targeting the Ataxia Telangiectasia Mutated-null Phenotype in Chronic Lymphocytic Leukemia with Pro-oxidants

Agathanggelou, A. and Weston, V.J. and Perry, T. and Davies, N.J. and Skowronska, A. and Payne, D.T. and Fossey, J.S. and Oldreive, C.E. and Wei, W. and Pratt, G. and Parry, H. and Oscier, D. and Coles, Steven and Hole, P.S. and Darley, R.L. and McMahon, M. and Hayes, J.D. and Moss, P. and Stewart, G. and Taylor, M. and Stankovic, T. (2015) Targeting the Ataxia Telangiectasia Mutated-null Phenotype in Chronic Lymphocytic Leukemia with Pro-oxidants. Haematologica, 100 (8). pp. 1076-1085. ISSN Print: 0390-6078 Online: 1592-8721

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Abstract

Inactivation of the Ataxia Telangiectasia Mutated gene in chronic lymphocytic leukemia results in resistance to p53-dependent apoptosis and inferior responses to treatment with DNA damaging agents. Hence, p53-independent strategies are required to target Ataxia Telangiectasia Mutated-deficient chronic lymphocytic leukemia. As Ataxia Telangiectasia Mutated has been implicated in redox homeostasis, we investigated the effect of the Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia genotype on cellular responses to oxidative stress with a view to therapeutic targeting. We found that in comparison to Ataxia Telangiectasia Mutated-wild type chronic lymphocytic leukemia, pro-oxidant treatment of Ataxia Telangiectasia Mutated-null cells led to reduced binding of NF-E2 p45-related factor-2 to antioxidant response elements and thus decreased expression of target genes. Furthermore, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia cells contained lower levels of antioxidants and elevated mitochondrial reactive oxygen species. Consequently, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia, but not tumours with 11q deletion or TP53 mutations, exhibited differentially increased sensitivity to pro-oxidants both in vitro and in vivo. We found that cell death was mediated by a p53- and caspase-independent mechanism associated with apoptosis inducing factor activity. Together, these data suggest that defective redox-homeostasis represents an attractive therapeutic target for Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia.

Item Type: Article
Uncontrolled Keywords: chronic lymphocytic leukemia, ATM, chemoresistant, oxidative stress, NRF2
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Academic Departments > Institute of Science and the Environment
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Copyright Info: Open Access journal
Depositing User: Steven Coles
Date Deposited: 13 Sep 2017 14:27
Last Modified: 14 Sep 2017 10:51
URI: https://eprints.worc.ac.uk/id/eprint/5875

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