The Myeloid Translocation Gene (MTG) family was first discovered through the (8;21) translocation that leads to acute myeloid leukemia by fusing nearly all of Myeloid Translocation Gene 8 (MTG8) to an N-terminal portion of Acute Myeloid Leukemia 1 (AML1) and redirecting the normal function of MTG8 as a transcriptional co-repressor. The two other family members, Myeloid Translocation Gene 16 (MTG16) and Myeloid Tumor Gene Related-1 (MTGR1), are also implicated in leukemogenesis and function by forming corepressor complexes with proteins such as Nuclear Receptor Corepressor 1 (N-CoR) and histone deacetylases, recruiting them to transcription factor binding partners to regulate gene expression. To examine the physiological roles of Mtg16, we created a knock-out mouse model and found that deletion of Mtg16 perturbs hematopoietic stem cell function and affects both T and B-cell development, resulting in a reduced number of both developing thymocytes and mature B and T cells. Thorough characterization of the in vivo development of B and T cells found several changes throughout the development of both populations with the most significant changes in the stem, progenitor, and early lineage committed compartments. These changes are exacerbated after stress: both B and T cell development are nearly eliminated after bone marrow transplant and in vitro differentiation assays show striking deficits. While the defects to B and T cell development show similarity, mechanistic differences have become apparent. The defect in Mtg16(-/-) in vitro T cell development can be complimented with retroviral reintroduction of Mtg16 and we identified interactions with both the Notch Intracellular Domain and E2A as critical to the function of Mtg16 in specifying T-cell fate. The deficit in in vitro B-cell development in the absence of Mtg16 appears to be a growth deficit, and we have data to suggest that removal of p53 can overcome this deficit and restore in vitro growth. We hypothesize that through interactions with different transcription factors, Mtg16 regulates lymphoid lineage commitment, growth, and survival.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03152013-081851 |
| Date | 11 April 2013 |
| Creators | Hunt, Aubrey Ann Salvino |
| Contributors | Dr. Bruce Carter, Dr. Luc VanKaer, Dr. Scott Hiebert, Dr. Zu-Wen Sun, Dr. Utpal Dave |
| 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-03152013-081851/ |
| 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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