The role of reactive oxygen species in the accumulation of driver mutations in B cell acute lymphoblastic leukemia
Abstract
B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with recurrent mutations and high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine was tested for its ability to prolong lifespan of a mouse model of B-ALL and reduce frequency of mutations. Mice treated with 1g/L of N-acetylcysteine in drinking water were found to have delayed onset of B-ALL at 11 weeks of age and changes in gene expression relating to B cell development, calcium-apoptosis signaling, and pathways in cancer, although no differences in lifespan were observed. Tumours from treated mice had 100% incidence of pseudokinase domain mutations in Jak1 or Jak3. These results indicate that tumours in treated mice develop later in life but become more aggressive than control tumours and that JAK mutations may act as drivers of leukemogenesis in the presence of lower levels of ROS.