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, Hole, Paul Spencer, Darley, Richard Lawrence ![]() |
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 tumors 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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Date Type: | Publication |
Status: | Published |
Schools: | Medicine |
Subjects: | R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
Publisher: | Ferrata Storti Foundation |
ISSN: | 0390-6078 |
Date of Acceptance: | 25 March 2015 |
Last Modified: | 31 Oct 2022 10:23 |
URI: | https://orca.cardiff.ac.uk/id/eprint/84643 |
Citation Data
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