Increase in mutant frequencies in mice expressing the BCR-ABL activated tyrosine kinase

The acquisition of the Philadelphia (Ph) chromosome (or BCR-ABL translocati on) represents a detrimental pathophysiological event in humans. The activa ted tyrosine kinases, which are produced by this translocation, are associa ted with fatal hematological malignancies. The initial molecular dissection of BCR-ABL has linked the expression of this constitutively activated kina se with enhanced genomic instability. We directly evaluated the consequence of BCR-ABL expression on genomic instability using the Big Blue in vivo mu tagenesis mouse system. We report that the expression of BCR-ABL in both sp leens and kidneys confers a mutator phenotype represented by a statisticall y significant elevation in mutant frequencies.