Abstract

Ataxia telangiectasia (A-T) is an autosomal recessive disorder characterized by immunodeficiency, progressive cerebellar ataxia, oculocutaneous telangiectasia, defective spermatogenesis, premature aging and high incidence of lymphoma. A-T is caused by the mutational inactivation of the “ataxia telangiectasia mutated” (ATM) gene. Ataxia telangiectasia mutated (ATM) plays a pivotal role in maintenance of genomic stability.

Both A-T patients and Atm−/− mice show humeral and cellular immune defects, including thymic hypoplasia, low number of T-cells and deficiencies of Ig levels. It was originally believed that ATM was not essential for V(D)J recombination in T and B cells, a process which is mediated largely by the nonhomologous end-joining (NHEJ) pathway of DNA repair. However, several studies have revealed that ATM contributes to the prevention of interchromosomal translocations arising from aberrant V(D)J recombination. Thus, it remains unclear how ATM contributes to development of lymphocytes and prevention of lymphoma. It has been shown that deficient ATM function leads to abnormal reactive oxygen species (ROS) control. Several papers reported evidences for increased oxidative stress in tissues from A-T patients or Atm−/− mice, although the mechanism by which ATM regulates ROS level is unclear. Further, abnormalities in the levels and function of antioxidant systems in ATM-deficient cells have been reported. It has been assumed that increased ROS or abnormal response to ROS may contributes to neurodegenerative diseases and premature aging observed in A-T patients. We previously reported a critical role for ATM in stem cell self-renewal due to the effects of this kinase on the regulation of ROS during hematopoiesis. Treatment with the anti-oxidative agent N-acetyl-L-cystine (NAC) prevented the bone marrow failure observed in Atm−/− mice. It was reported that antioxidant prevented tumor development in p53−/− mice. Thus, appropriate ROS control is critical for clinical and cellular phenotypes of tumor-prone disorders.

Here we show that a primary cause of immunodeficiency and lymphomagenesis in Atm−/− mice is the elevation of reactive oxygen species (ROS) present in these mutants. Reduction of ROS by NAC prevented the emergence of the senescent phenotype in mouse embryonic fibroblasts and hypersensitivity to total body irradiation in Atm−/− mice. The impairment of immunoglobulin class switch recombination (CSR) seen in Atm−/− mice was also mitigated by NAC, indicating that ROS elevation inhibits physiological DSBs rejoining in vivo. Significantly, in vivo treatment of Atm−/− mice with NAC restored normal T cell development, inhibited aberrant V(D)J recombination, and prevented thymic lymphomagenesis. We conclude that ATM-mediated ROS regulation is essential for the maintenance of genomic stability that prevents immunodeficiency and tumorigenesis. These findings may contribute to effective treatment of A-T patients for prevention of symptoms.

Disclosure: No relevant conflicts of interest to declare.

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