| Description |
Note: To agree with NCBI nomenclature guidelines, human gene abbreviations are italicized and capitalized; human protein abbreviations are non-italicized and capitalized, and zebrafish gene abbreviations are italicized in lowercase. T lymphocytes, or T-cells, are blood cells that normally fight viral, fungal, and other infections. T-cell Acute Lymphoblastic Leukemia (T-ALL) is a cancer that can arise from these cells, and is caused by an overgrowth of abnormal T-cells. It is an aggressive cancer that progresses quickly if left untreated. While effective treatments for T-ALL exist, approximately 20% of pediatric and 50% of adult T-ALL patients will later relapse, and most of these ultimately die of their disease. My project uses zebrafish (Danio rerio) that are prone to developing T-ALL to test investigational agents for TALL treatment. Such studies are called "pre-clinical" trials. Fish used in this project express Green Fluorescent Protein (GFP) in their T-cells, making it possible to identify their cancers using a fluorescent microscope. Fish with T-ALL have large GFP+ tumors in the area of the thymus or exhibit GFP throughout the body. Healthy fish have GFP. exclusively in their thymus. HCI-2084 is an experimental drug developed by the Sharma lab at the University of Utah's Huntsman Cancer Institute, and UNC569 is an experimental drug developed by the Graham lab at University of Colorado-Denver. UNC569 inhibits human MER, a receptor tyrosine kinase highly expressed in human and zebrafish T-ALL cells, and HCI-2084 inhibits both MER and AXL, a second highly expressed T-ALL receptor tyrosine kinase, as well as the Aurora family kinases, which are frequently overexpressed by many leukemias. We hypothesized that these drugs would also inhibit the zebrafish homologues of these human proteins, and in doing so, could effectively treat zebrafish T-ALL. Drug treatments were performed by housing fish in water containing the agents being tested. To determine if trials were effective, fish were examined by fluorescent microscopy to determine if T-ALL had regressed. Our results demonstrate that HCI-2084 and UNC569 are potent therapeutic agents against vertebrate T-ALL and should be further investigated as potential drugs for treatment of human T-ALL. |
