In chronic myelogenous leukemia (CML), activation of BCR-ABL, the product of the bcr-abl chimeric gene, leads to constitutive activation of pathways that increase genomic instability through endogenous production of reactive oxygen species (ROS) that cause oxidative DNA damage and inactivate the function of repair proteins leading to unfaithful DNA repair. If misrepaired, oxidative DNA damage, such as 8-oxoguanine (8-oxoG), may result in point mutations and/or DNA double-strand breaks (DSBs) leading to drug resistance to the BCR-ABL kinase inhibitor imatinib mesylate (IM) and accumulation of chromosomal aberrations associated with malignant CML progression from a benign chronic phase (CP) to a fatal blast phase (BP). To determine which population of CML-CP cells, leukemia stem cells (LSCs) and/or leukemia progenitor cells (LPCs), displays elevated levels of ROS and oxidative DNA damage, and whether these elevated levels of ROS and oxidative DNA damage in CML-CP subpopulations result in the accumulation of genomic instability, we employed the tetracycline-inducible SCLtTA/BCR-ABL transgenic mouse model. We showed that LSCs, including the quiescent subpopulation, but not LPCs, displayed elevated levels of ROS and oxidative DNA damage, perhaps due to deregulated expression of genes involved in ROS metabolism, resulting in genomic instability manifested by both point mutations and genetic alterations. We also examined the effect of IM on ROS, oxidative DNA damage and genomic instability displayed by CML-CP subpopulations, and determined that elevated ROS and oxidative DNA damage were not inhibited by IM in quiescent LSCs, nor was genomic instability and deregulated gene expression prevented. To explore underlying mechanisms, i.e. BCR-ABL expression levels, by which CML-CP cells accumulate genomic instability, we examined the effect of low and high BCR-ABL expression on ROS and oxidative DNA damage in BCR-ABL-transduced human CD34+ cells. We detected elevated ROS and oxidative DNA damage in high BCR-ABL-expressing CD34+ cells compared to low BCR-ABL-expressing cells. Furthermore, BCR-ABL exerted a kinase-dependent effect on ROS-dependent DNA damage. These data support the hypothesis that genomic instability may originate from LSCs, but do not exclude the potential role of LPCs, and may have important clinical implications for CML treatment since additional genetic aberrations that encode primary resistance may protect LSCs, including the quiescent subpopulation, from eradication by tyrosine kinase inhibitors (TKIs), and the continuous accumulation of genetic errors may trigger disease relapse and progression. / Microbiology and Immunology
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/828 |
| Date | January 2013 |
| Creators | Bolton, Elisabeth Spring |
| Contributors | Skorski, Tomasz, Tsygankov, Alexander Y., Soprano, Kenneth J., Liebermann, Dan A., 1949-, Shore, Scott K. |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 92 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/810, Theses and Dissertations |
Page generated in 0.002 seconds