GATA3 is an essential transcription factor for T lymphopoiesis but elevated expression of GATA3 can derail T cell differentiation and promote transformation. The E2A transcription factors are also required for normal T cell differentiation and deletion of E2A, or inhibition of E2A function, results in hyper-proliferation of T cell progenitors and development of T cell lymphoma in mice and T lymphocyte acute lymphoblastic leukemia (T-ALL) in humans. We have previously shown that lymphomas arising in E2A- /- mice share with the majority of T-ALL a deregulation of the Notch signaling pathway. However, how reduced E2A activity results in susceptibility to T cell transformation remains unknown. We recently found that early in thymocyte development E2A is required to limit expression of Gata3 and that heterozygous deletion of Gata3 in E2A-/- mice partially restores T cell differentiation and prevents T cell progenitor hyper- proliferation. Here we propose experiments to test the hypothesis that deregulation of GATA3 leads to sustained repression of cell cycle inhibitors that predispose T cell progenitors to hyper-proliferation and T cell transformation. Our hypothesis predicts that tight regulation of GATA3 is necessary to allow T cell differentiation without transformation.
Our experiments are intended to reveal the underlying basis for transformation of T cell progenitors in a model of lymphomagenesis that has many commonalities with human T- ALL. While childhood ALL has a relatively good prognosis, some subsets of this disease, and relapse T-ALL are hard to treat. In addition, adult patients with T-ALL have a poor prognosis. Understanding the mechanisms that predispose to leukemogenesis is necessary to improve our ability to identify conditions favorable to emergence of disease and thereby improve methods for early detection. In addition, our experiments will provide insight into how the transformation process is initiated and which proteins might be future targets for therapy in T-ALL.
|Xu, Wei; Carr, Tiffany; Ramirez, Kevin et al. (2013) E2A transcription factors limit expression of Gata3 to facilitate T lymphocyte lineage commitment. Blood 121:1534-42|