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: 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 S Stewart, A Malcolm R Taylor, Tatjana Stankovic
• Journal: Haematologica (Haematologica) Vol. 100 Issue 8 Pg. 1076-85 (Aug 2015) ISSN: 1592-8721 [Electronic] Italy
• PMID: 25840602 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Ferrata Storti Foundation.

Chemical References

• Antioxidants
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Oxidants
• Reactive Oxygen Species
• Tumor Suppressor Protein p53
• Superoxides
• Ataxia Telangiectasia Mutated Proteins
• Caspases

Topics

• Animals
• Antioxidants (metabolism)
• Apoptosis
• Ataxia Telangiectasia Mutated Proteins (genetics)
• Caspases (metabolism)
• Disease Models, Animal
• Gene Expression Regulation, Leukemic
• Homozygote
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (genetics, metabolism)
• Mitochondria (metabolism)
• Mutation
• NF-E2-Related Factor 2 (genetics, metabolism)
• Oxidants (metabolism)
• Phenotype
• Protein Binding
• Reactive Oxygen Species (metabolism)
• Response Elements
• Superoxides (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays