Measurement of genomic instability in preleukemic P190BCR/ABL transgenic mice using inter-simple sequence repeat...

BCR/ABL associated leukemias are characterized by a high degree of chromosomal and genomic instability. The genomic instability is usually associated with disease progression, as in chronic myelogenous leukemia or a poor prognosis as observed in hallmark Philadelphia chromosome-positive acute lymphoblastic leukemia. It is unclear whether the phenotype of genomic instability is a primary consequence of Bcr/Abl expression or if it is secondarily acquired in the multistep process of tumor evolution. To address this issue, we measured the frequency of insertions and deletions in P190(BCR/ABL) transgenic mice. These mice ubiquitously express Bcr/Abl for an average of 3 months before developing B-cell type lymphoma/leukemia. Genome scanning for insertions and deletions in samples of DNA extracted from kidney and spleen tissues taken from preleukemic animals was performed using the inter-simple sequence repeat PCR. We observed an increased frequency of insertions and deletions in the tissues of preleukemic animals, which could be partially reversed with the c-Abl specific inhibitor STI571. These results suggest that the expression of Bcr/Abl can directly induce a mutator phenotype that antedates overt neoplastic transformation, and that STI571 appears to be capable of reversing this effect.