Adult T-cell leukemia/lymphoma (ATLL) is an incurable peripheral T-cell malignancy where most patients succumb within the first year of diagnosis. Development of ATLL requires human T-cell lymphotrophic virus type 1 (HTLV-I) retroviral infection followed by accumulation of somatic mutations and changes in gene expression. The discovery of genes and pathways involved in the initiation of ATLL may provide novel therapeutic targets for treatment of this fatal disease. Since the IL-2 signaling pathway plays an important role in ATLL development, mutational analysis of IL-2 signaling pathway components should yield a better understanding of disease progression and outcome. Janus kinase 3 (JAK3), a nonreceptor tyrosine kinase is a key kinase upstream in the IL-2 signaling pathway. Activating somatic mutations in JAK3 have been described in leukemias and lymphomas including acute megakaryoblastic leukemia and natural killer/T-cell lymphoma. Three mutations in the regulatory FERM domain of JAK3 were identified in four of the thirty-six ATLL patients screened and no mutations were found in the twenty-four screened ethnically matched controls. These somatic, missense mutations occurred in the amino terminal regulatory FERM domain. JAK3 FERM domain may play an autoregulatory role by inhibiting kinase activity in the absence of IL-2. In cell culture assays all three FERM domain mutations induce gain of function in JAK3 and can be inhibited with a JAK specific kinase inhibitor, tofacitinib. One of the JAK3 FERM domain mutations (E183G) was characterized in vivo and found to be oncogenic in cooperation with the loss of cell cycle regulatory proteins p16(INK4a) and p14(ARF). These findings emphasize the importance of JAK3 activation in ATLL development and offer a novel therapeutic target for this incurable disease.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-01072013-121936 |
| Date | 23 May 2013 |
| Creators | Elliott, Natalina Elizabeth |
| Contributors | Utpal Davé MD, Stephen Brandt MD, Scott Hiebert PhD, William Pao MD PhD |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-01072013-121936/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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