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IntroductionThe BCR/ABL gene is derived from the relocation of a portion of c-ABL gene from chromosome 9 to the portion of BCR gene locus on chromosome 22 (t(9;22), Philadelphia chromosome [Ph]) and is present in most chronic myeloid leukemia (CML) and in a cohort of acute lymphocytic leukemia (ALL) patients. 1 BCR/ABL oncogenic tyrosine kinase (a product of BCR/ABL chimeric gene) exhibits 2 complementary roles in cancer. The first and best-characterized is stimulation of signaling pathways that eventually induce growth factor independence and affect the adhesive and invasive capability of leukemia cells. The second is the modulation of responses to DNA damage, rendering cells resistant to genotoxic therapies and causing genomic instability. 2 Clinical observations and experimental findings suggest that BCR/ABL-induced genomic instability may lead to mutations and chromosomal translocations frequently observed during the transition from a relatively benign CML chronic phase (CML-CP) to an aggressive blast crisis (CML-BC). 3 In addition, genomic instability also is manifested by numerous mutations detected in the BCR/ABL gene encoding for resistance to imatinib mesylate (IM). 4 IM, a selective inhibitor of ABL kinase activity, revolutionized the treatment of BCR/ABL-positive leukemias. 5 Unfortunately, clinical and experimental observations reveal that resistance to IM is increasingly problematic. 4 Although the rate of progression of newly diagnosed CML-CP patients on IM is about 4% per year, IM resistance obscures this otherwise successful oncogenetargeted therapy. 6 BCR/ABL kinase mutations appear to be the most frequent cause of acquired resistance to IM; resistant cells also may exhibit genomic amplification of nonmutated BCR/ABL and BCR/ABL independence due to overexpression of LYN kinase. 4,7 Mutations also were detected in CML-CP patients before IM treatment, thus arguing for genetic instability early in the disease. Therefore, the BCR/ABL gene appears to be a casualty of genomic instability promoted by its own product-the BCR/ABL kinase.Mutations usually result from enhanced DNA damage and/or deregulated mechanisms responsible for DNA repair. 8,9 Much endogenous DNA damage arises from intermediates of oxygen reduction. Oxygen is metabolized inside the cell by a series of one-electron reductions with the generation of reactive and potentially damaging intermediates called reactive oxygen species (ROS), 10 primarily generated by the mitochondrial respiratory chain (MRC). 11 ROS units usually are short-lived and strike only molecules that are close in space and time, such as free nucleotides, which are subsequently incorporated into DNA during replication by unfaithful polymerases. 9 Examples of ROS derivatives include 7,8-dihydro-8-oxo-2Ј-deoxyguanosine (8-oxoG), 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy), thymidine glycol, and 5-hydroxycytosine. 12 BCR/ABL-mediated generation of ROS by MRC 13 combined with aberrant regulation of DNA repair pathways 14 may contribute to the mutator phenotype displa...