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, Stankovic Tatjana
School of Cancer Sciences, University of Birmingham.
School of Chemistry, University of Birmingham.
Haematologica. 2015 Aug;100(8):1076-85. doi: 10.3324/haematol.2014.115170. Epub 2015 Apr 3.
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.
共济失调毛细血管扩张症突变基因在慢性淋巴细胞白血病中的失活导致对p53依赖性凋亡的抗性以及对DNA损伤剂治疗的反应较差。因此，需要采用不依赖p53的策略来靶向共济失调毛细血管扩张症突变缺陷型慢性淋巴细胞白血病。由于共济失调毛细血管扩张症突变与氧化还原稳态有关，我们研究了共济失调毛细血管扩张症突变缺失型慢性淋巴细胞白血病基因型对细胞氧化应激反应的影响，以期进行治疗靶向。我们发现，与共济失调毛细血管扩张症突变野生型慢性淋巴细胞白血病相比，对共济失调毛细血管扩张症突变缺失型细胞进行促氧化剂处理会导致NF-E2 p45相关因子-2与抗氧化反应元件的结合减少，从而降低靶基因的表达。此外，共济失调毛细血管扩张症突变缺失型慢性淋巴细胞白血病细胞中抗氧化剂水平较低，线粒体活性氧升高。因此，共济失调毛细血管扩张症突变缺失型慢性淋巴细胞白血病，而非伴有11q缺失或TP53突变的肿瘤，在体外和体内对促氧化剂的敏感性均有差异增加。我们发现细胞死亡是由与凋亡诱导因子活性相关的不依赖p53和半胱天冬酶的机制介导的。总之，这些数据表明氧化还原稳态缺陷是共济失调毛细血管扩张症突变缺失型慢性淋巴细胞白血病一个有吸引力的治疗靶点。
