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...

Chromosomal translocations are responsible for the appearance of oncogenes encoding fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGF␤R, TEL/TRKC(L), and NPM/ALK (6, 35). BCR/ABL is derived from relocation of the portion of the c-ABL gene from chromosome 9 to the portion of the BCR gene locus on chromosome 22 [t(9;22)] and is present in most chronic myelogenous leukemia (CML) patients and a cohort of acute lymphocytic leukemia (ALL) patients (11,19,64). TEL/ABL results from a t(9;12) translocation reported in ALL, acute myelogenous leukemia (AML), and atypical CML (35) and consists of the amino-terminal fragment of the TEL domain fused in-frame with exon 2 of ABL (24). TEL/JAK2 was characterized as a product of a t(9;12) translocation which includes the TEL oligomerization domain and JAK2 catalytic domain (37) and was found in ALL (37, 51). TEL/PDGF␤R is associated with a t(5;12) translocation which juxtaposes the amino-terminal region of TEL with the transmembrane and tyrosine kinase domains of the platelet-derived growth factor receptor ␤ (23). TEL/PDGF␤R was found in chronic myelomonocytic leukemia (35). The consequence of t(12;15) is expression of the TEL/TRKC fusion tyrosine kinase associated with AML, infantile fibrosarcoma, and congenital mesoblastic nephroma (41). The TEL/TRKC fusion in AML [TEL/TRKC(L)] includes exons 1 to 4 of the TEL gene fused in frame to the tyrosine kinase domain of TRKC lacking a 42-bp exon near the C terminus of the TRKC moiety. NPM/ALK, formed by the t(2;5) translocation, was implicated in the pathogenesis of anaplastic large cell lymphoma (38). The NPM/ALK fusion gene encodes a 75-kDa hybrid protein that contains the aminoterminal portion of the nucleolar phosphoprotein nucleophosmin (NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase ALK (anaplastic lymphoma kinase) (44). These FTKs (BCR/ABL-related FTKs) show structural similarities, which include an amino-terminal oligomerization domain responsible for constitutive oligomerization and activation of the associated tyrosine kinase of the carboxy-terminal fusion partner.FTKs and other oncogenic tyrosine kinases such as v-Src and HER-2/neu activate multiple signaling pathways responsible for protection from apoptosis, induction of growth factor-independent proliferation, transformation, and resistance to therapeutic drugs and to ␥-radiation (25,41,43,53,54,61,85). Resistance to DNA-damaging agents is a cause for failure in the therapy of human cancer, including hematological malignancies. Several mechanisms of resistance to DNA damage