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

Agathanggelou, Angelo and Weston, Victoria J and Perry, Tracey and Davies, Nicholas J and Skowronska, Anna and Payne, Daniel T and Fossey, John S and Oldreive, Ceri E and Wei, Wenbin and Pratt, Guy and Parry, Helen and Oscier, David and Coles, Steve J and Hole, Paul S and Darley, Richard L and McMahon, Michael and Hayes, John D and Moss, Paul and Stewart, Grant S and 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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Official URL: http://www.haematologica.org/content/100/8/1076.fu...

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.heartofengland.nhs.uk/id/eprint/1089

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