The Bcr-abl translocation arises from a reciprocal translocation between chromosomes 9 and 22 and results in the augmentation of the tyrosine kinase activity of c-Abl. Chronic myelogenous leukemia (CML) is one of several hematological malignancies associated with Bcr-abl expression. The pathogenesis of CML, associated with P210Bcr-abl, is bi-phasic consisting of an initial chronic phase followed by a severe terminal phase referred to as acute blast crisis. The chronic phase of the disease is characterized by granulocytic hyperplasia but in which normal hematologic maturation is still intact. Patients ultimately enter the terminal blast crisis where hematologic maturation is lost, resulting in the accumulation of immature blast cells and a severe immuno-compromised state. Progression to the blast terminal phase is associated with genomic instability demonstrated by the accumulation of genetic and cytogenetic abnormalities. Results from in vitro cell line systems expressing Bcr-abl have suggested that the loss of cell-cycle arrest and induction of apoptosis, as a result of genotoxic stress, might be responsible for this phenotype. In this study, I utilized a transgenic mouse model which expresses P190Bcr-abl to extend those observations to an in vivo model for leukemia. I observed normal cell-cycle arrest and induction of apoptosis following the induction of DNA damage. However, using the Big Blue in vivo mutagenesis mouse assay system, I evaluated genomic instability in P190Bcr-abl mice by measuring mutation frequencies in vivo. I observed an increase in mutation frequencies in spleens and kidneys from P190Bcr-abl mice. This Bcr-abl-induced mutator phenotype may explain the inherent genomic instability associated with the progression of CML and other diseases associated with the expression of activated tyrosine kinases.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.35483 |
| Date | January 1998 |
| Creators | Salloukh, Hashem F. |
| Contributors | Laneuville, Peirre (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001652194, proquestno: NQ50254, Theses scanned by UMI/ProQuest. |
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