title: Targeting the Ataxia Telangiectasia Mutated-null phenotype in chronic lymphocytic leukemia with pro-oxidants.
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.
authors.affiliation: School of Cancer Sciences, University of Birmingham.
authors.forename: Angelo
authors.initials: A
authors.lastname: Agathanggelou
authors.affiliation: School of Cancer Sciences, University of Birmingham.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Weston
authors.affiliation: School of Cancer Sciences, University of Birmingham.
authors.forename: Tracey
authors.initials: T
authors.lastname: Perry
authors.affiliation: School of Cancer Sciences, University of Birmingham.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Davies
authors.affiliation: School of Cancer Sciences, University of Birmingham.
authors.forename: Anna
authors.initials: A
authors.lastname: Skowronska
authors.affiliation: School of Chemistry, University of Birmingham.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Payne
authors.affiliation: School of Chemistry, University of Birmingham.
authors.forename: John S
authors.initials: JS
authors.lastname: Fossey
authors.affiliation: School of Cancer Sciences, University of Birmingham.
authors.forename: Ceri E
authors.initials: CE
authors.lastname: Oldreive
authors.affiliation: School of Cancer Sciences, University of Birmingham.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Wei
authors.affiliation: School of Cancer Sciences, University of Birmingham Haematology Department, Birmingham Heartlands Hospital.
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.affiliation: Haematology Department, Birmingham Heartlands Hospital.
authors.forename: Helen
authors.initials: H
authors.lastname: Parry
authors.affiliation: Haematology Department, Royal Bournemouth Hospital, Dorset.
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.affiliation: Department of Haematology, Institute of Cancer and Genetics, Cardiff University School of Medicine, Cardiff.
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Coles
authors.affiliation: Department of Haematology, Institute of Cancer and Genetics, Cardiff University School of Medicine, Cardiff.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Hole
authors.affiliation: Department of Haematology, Institute of Cancer and Genetics, Cardiff University School of Medicine, Cardiff.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Darley
authors.affiliation: Medical Research Institute, University of Dundee, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: McMahon
authors.affiliation: Medical Research Institute, University of Dundee, UK.
authors.forename: John D
authors.initials: JD
authors.lastname: Hayes
authors.affiliation: School of Cancer Sciences, University of Birmingham.
authors.forename: Paul
authors.initials: P
authors.lastname: Moss
authors.affiliation: School of Cancer Sciences, University of Birmingham.
authors.forename: Grant S
authors.initials: GS
authors.lastname: Stewart
authors.affiliation: School of Cancer Sciences, University of Birmingham.
authors.forename: A Malcolm R
authors.initials: AM
authors.lastname: Taylor
authors.affiliation: School of Cancer Sciences, University of Birmingham t.stankovic@bham.ac.uk.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D015973:Gene Expression Regulation, Leukemic; D006720:Homozygote; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements; D013481:Superoxides / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016877:Oxidants; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D013481:Superoxides; D064007:Ataxia Telangiectasia Mutated Proteins; D020169:Caspases
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