| Notes: | Advisor: Barbara L. Kee.
Thesis (Ph.D.)--The University of Chicago, Division of the Biological Sciences, and the Pritzker School of Medicine, Committee on Cancer Biology, 2010.
Dissertation Abstracts International, Volume: 71-07, Section: B, page: 4165.
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| Summary: | The E2A transcription factors are required for proper T lymphopoiesis and to prevent T lymphocyte progenitor transformation. Loss of E2A leads to a decreased number of lymphoid-primed multipotent progenitors (LMPPs) in the bone marrow and T cell progenitors in the thymus. Ectopic expression of E2A proteins in E2A-/- lymphoma results in growth arrest and apoptosis, indicating that these cells remain responsive to the targets of E2A. In this study we showed that E2A-/- progenitor cells from both adult thymus and fetal liver poorly differentiated into committed DN3 cells in vitro but undertook a NK cell program. We found that E2A-/- DN2 cells as well as fetal-derived T cell precursors overproduced Gata3, a transcriptional factor that is also essential for T cell development, however high levels of Gata3 were reported to block T cell lineage commitment and divert progenitors to alternative cell fate. We showed that genetic ablation of one allele of Gata3 restored T cell differentiation in vitro and in vivo in the absence of E2A, suggesting Gata3 expression should be tightly controlled to ensure normal T cell development. Theses findings demonstrated a critical role for E2A in facilitating T cell lineage commitment by restraining the expression of Gata3. We also identified, in this study, the transcriptional repressor growth factor independent 1b (Gfi1b) as a direct target of E2A which promotes growth arrest and apoptosis in E2A-/- lymphomas. Gfi1b represses the expression of Gata3 which is required for the survival of lymphomas and T cell progenitors. We showed that ectopic expression of Gata3 in the T cell lymphomas promotes the expression of Gfi1b, suggesting these proteins may function in an auto regulatory loop to maintain appropriate levels of Gata3. Taken together, our study identified a transcriptional regulatory pathway in which E2A proteins promote T cell lineage commitment as well as prevent lymphoma cell expansion through modulation of Gata3 expression.
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