Measurement of genomic instability in preleukemic P190BCR/ABL transgenic mice using inter-simple sequence repeat polymerase chain reaction.
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.
Brain
Julia M
JM
Department of Medicine and the Division of Hematology and Molecular Oncology Group, McGill University, Montreal, Quebec, Canada.
Goodyer
Nathaniel
N
Laneuville
Pierre
P
D000818:Animals; D001483:Base Sequence; D001549:Benzamides; D016044:Fusion Proteins, bcr-abl / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D000068877:Imatinib Mesylate; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010879:Piperazines / Q000627:therapeutic use; D016133:Polymerase Chain Reaction / Q000379:methods*; D011289:Preleukemia / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use; D013154:Spleen / Q000378:metabolism
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl