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

Agathanggelou, Angelo, Weston, Victoria J, Perry, Tracey, Davies, Nicholas J, Skowronska, Anna, Payne, Daniel T, Fossey, John S, Oldreive, Ceri E, Wei, Wenbin, Pratt, Guy, Parry, Helen, Oscier, David, Coles, Steve J, Hole, Paul S, Darley, Richard L, McMahon, Michael, Hayes, John D, Moss, Paul, Stewart, Grant S, Taylor, A Malcolm R and Stankovic, Tatjana (2015) Targeting the Ataxia Telangiectasia Mutated-null phenotype in chronic lymphocytic leukemia with pro-oxidants. Haematologica, 100 (8). pp. 1076-85. ISSN 1592-8721. This article is accessible to all HEFT staff and students via ASK Discovery Tool http://search.ebscohost.com/login.aspx?authtype=guest&custid=ns123736&groupid=main by using Athens login

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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 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
Additional Information: This article is accessible to all HEFT staff and students via ASK Discovery Tool http://search.ebscohost.com/login.aspx?authtype=guest&custid=ns123736&groupid=main by using Athens login
Subjects: WH Haemic and lymphatic systems. Haematology
Divisions: Planned IP Care > Oncology and Clinical Haematology
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Depositing User: Preeti Puligari
Date Deposited: 06 Jan 2017 14:30
Last Modified: 06 Jan 2017 14:31
URI: http://www.repository.uhblibrary.co.uk/id/eprint/1089

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