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BCR/ABL Inhibits Mismatch Repair to Protect from Apoptosis and Induce Point Mutations

Departments of ¹ Microbiology and Immunology and ² Pediatrics/Hematology, Temple University, Philadelphia, Pennsylvania; ³ Department of Immunology, Medical University of Warsaw; ⁴ Department of Hematology, Institute of Hematology and Blood Transfusion, Warsaw, Poland; and ⁵ Department of Molecular Genetics, University of Lodz, Lodz, Poland

Requests for reprints: Tomasz Skorski, Department of Microbiology and Immunology, School of Medicine, Temple University, Medical Research Building, Room 548A, 3400 North Broad Street, Philadelphia, PA 19140. Phone: 215-707-9157; Fax: 215-707-9160; E-mail: tskorski{at}temple.edu.

Key Words: BCR/ABL • genomic instability • mismatch repair

BCR/ABL kinase–positive chronic myelogenous leukemia (CML) cells display genomic instability leading to point mutations in various genes including bcr/abl and p53, eventually causing resistance to imatinib and malignant progression of the disease. Mismatch repair (MMR) is responsible for detecting misincorporated nucleotides, resulting in excision repair before point mutations occur and/or induction of apoptosis to avoid propagation of cells carrying excessive DNA lesions. To assess MMR activity in CML, we used an in vivo assay using the plasmid substrate containing enhanced green fluorescent protein (EGFP) gene corrupted by T:G mismatch in the start codon; therefore, MMR restores EGFP expression. The efficacy of MMR was reduced 2-fold in BCR/ABL-positive cell lines and CD34⁺ CML cells compared with normal counterparts. MMR was also challenged by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), which generates O⁶-methylguanine and O⁴-methylthymine recognized by MMR system. Impaired MMR activity in leukemia cells was associated with better survival, accumulation of p53 but not of p73, and lack of activation of caspase 3 after MNNG treatment. In contrast, parental cells displayed accumulation of p53, p73, and activation of caspase 3, resulting in cell death. Ouabain-resistance test detecting mutations in the Na⁺/K⁺ ATPase was used to investigate the effect of BCR/ABL kinase–mediated inhibition of MMR on mutagenesis. BCR/ABL-positive cells surviving the treatment with MNNG displayed 15-fold higher mutation frequency than parental counterparts and predominantly G:CA:T and A:TG:C mutator phenotype typical for MNNG-induced unrepaired lesions. In conclusion, these results suggest that BCR/ABL kinase abrogates MMR activity to inhibit apoptosis and induce mutator phenotype. [Cancer Res 2008;68(8):2576–80]