Mutator phenotype of BCR-ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase beta

Chronic myelogenous leukemia (CML) is characterized by the Philadelphia chr omosome resulting from the translocation t(9-22) producing the chimeric 190 and 210 kDa BCR-ABL fusion proteins. Evolution of the CML to the more aggr essive acute myelogenous leukemia (AML) is accompanied by increased cellula r proliferation and genomic instability at the cytogenetic level. We hypoth ezised that genomic instability at the nucleotide level and spontaneous err or in DNA replication may also contribute to the evolution of CML to AML. M urine Ba/F3 cell line was transfected with the p190 and p210-encoding BCR-A BL oncogenes, and spontaneous mutation frequency at the Na-K-ATPase and the hypoxanthine guanine phosphoribosyl transferase (HPRT) loci were measured. A significant 3-5-fold increase in mutation frequency for the transfected cells relative to the untransfected control cells was found. Furthermore, w e observed that BCR-ABL transfection induced an overexpression of DNA polym erase beta, the most inaccurate of the mammalian DNA polymerases, as well a s an increase in its activity, suggesting that inaccuracy of DNA replicatio n may account for the observed mutator phenotype. These data suggest that t he Philadelphia abnormality confers a mutator phenotype and may have implic ations for the potential role of DNA polymerase beta in this process.