LIM domain Only-2 (LMO2) is a T cell oncogene whose molecular mechanism for T-cell transformation still remains to be elucidated. There are two hypotheses that could explain how the enforced expression of LMO2 induces T-cell Acute Lymphoblastic Leukemia (T-ALL). The first hypothesis is that LMO2 enforced expression results in the functional deficiency of E2A proteins. LMO2 overexpression correlates with the loss of E2A proteins, or Heb, suggesting that LMO2 functions by creating a deficiency of E2A either by redirection, sequestration, or turnover. To test this hypothesis, we enforced the expression ofE47Lmo2-induced T-ALL cell lines using an E47/estrogen receptor fusion construct that could be forced to homodimerize with 4-hydroxytamoxifen (4HT). We discovered that forced homodimerization triggered a G1 cell cycle growth arrest in 2 of the 4 lines tested. Transcriptome analysis suggested that E47 has remarkably diverse effects in T-ALL but that functional deficiency of E47 is not a universal feature of Lmo2-induced T-ALL.
The second hypothesis, suggests that Lmo2 enforced expression results in transcriptional regulation of genes needed for T-cell transformation. The gene of interest in our studies is Hematopoietically expressed homeobox (Hhex). Hhex is a T-cell oncogene that is frequently deregulated in murine retroviral insertional mutagenesis screens and its enforced expression induces T-cell leukemia in bone marrow transduction and transplantation experiments. To further understand Hhexs function, we induced a conditional knockout in floxed Hhex mice with the Vav-iCre transgene. Mice were viable and showed normal blood cell counts with highly efficient deletion of Hhex in all hematopoietic tissues. Most impressively, Hhex conditional knockout markedly prolonged T-ALL onset in CD2-Lmo2 transgenic mice. Hhex conditional knockouts also had a significant decrease in mature B cells in the spleen and bone marrow. Bone marrow transplant and thymic repopulation studies revealed that loss of Hhex is important not only B cell development but also early T cell development. Our experiments show that Hhex is a critical transcription factor in lymphoid development and in LMO2-induced T-ALL.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03082015-161612 |
| Date | 09 March 2015 |
| Creators | Goodings, Charnise Amoré |
| Contributors | Stephen Brandt, Utpal Davé, Scott Hiebert, Sandra Zinkel |
| 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-03082015-161612/ |
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