Targeting the Ataxia Telangiectasia Mutated-null phenotype in chronic lymphocytic leukemia with pro-oxidants

Angelo Agathanggelou, Victoria J. Weston, Tracey Perry, Nicholas J. Davies, Anna Skowronska, Daniel T. Payne, John S. Fossey, Ceri E. Oldreive, Wenbin Wei, Guy Pratt, Helen Parry, David Oscier, Steve J. Coles, Paul S. Hole, Richard L. Darley, Michael McMahon, John D. Hayes, Paul Moss, Grant Stewart, A. Malcolm R. TaylorTatjana Stankovic

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    7 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1076-1085
    Number of pages10
    JournalHaematologica
    Volume100
    Issue number8
    Early online date3 Apr 2015
    DOIs
    Publication statusPublished - Aug 2015

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  • Cite this

    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, S. J., Hole, P. S., Darley, R. L., McMahon, M., Hayes, J. D., Moss, P., Stewart, G., ... Stankovic, T. (2015). Targeting the Ataxia Telangiectasia Mutated-null phenotype in chronic lymphocytic leukemia with pro-oxidants. Haematologica, 100(8), 1076-1085. https://doi.org/10.3324/haematol.2014.115170