University of Worcester Worcester Research and Publications

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

Agathanggelou, A., Weston, V.J., Perry, T., Davies, N.J., Skowronska, A., Payne, D.T., Fossey, J.S., Oldreive, C.E., Wei, W., Pratt, G., Parry, H., Oscier, D., Coles, Steven ORCID:, Hole, P.S., Darley, R.L., McMahon, M., Hayes, J.D., Moss, P., Stewart, G., 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

haematol.2014.115170.full.pdf - Accepted Version

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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
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The full-text of the online published article can be accessed via the Official URL.

Uncontrolled Discrete Keywords: chronic lymphocytic leukemia, ATM, chemoresistant, oxidative stress, NRF2
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: College of Health, Life and Environmental Sciences > School 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: 17 Jun 2020 17:19

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