T cell development in the thymus and T cell activation are highly regulated processes, and dysregulation of genes and pathways involved in normal T cell development and activation can lead to the emergence of T cell leukemias and lymphomas. The molecular mechanisms that control normal T cell development are also involved in oncogenetic transformation, and understanding normal development may lead to new therapeutic targets for T cell leukemia and lymphoma. Our studies focus on the role of a novel protein, Shcbp1, in thymocyte development and in peripheral T cell responses and activation. Shcbp1 is upregulated in thymocyte that are highly proliferative, and is further upregulated after anti-CD3 stimulation in both immature thymocytes and mature T cells. Our preliminary evidence suggests that Shcbp1 may help regulate the proliferative burst that occurs during ?-selection, a developmental checkpoint that ensures proper expression and signaling through the TCR? chain. Additionally, our preliminary data suggests that Shcbp1 may regulate proliferation that occurs during the primary immune response. We will further investigate the role of Shcbp1 in T cell development and activation using a mouse with conditional deletion of Shcbp1 in the thymus, which will allow us to investigate the role of Shcbp1 in T cell development and peripheral T cell responses.
T cell leukemia and lymphomas are aggressive blood cancers and approximately 15-25% of all acute lymphoblastic leukemias (ALL) are T-cell. T cell acute lymphoblastic leukemia (T-ALL) arises in the thymus of thymocytes at known stages of development and eventually infiltrates the bone marrow, peripheral lymphoid system, and other organs. Although less understood, there is also a group of T cell lymphomas that arise from transformations of mature peripheral T cells. The molecular mechanisms that control normal T cell development and activation are also involved in oncogenetic transformation, and understanding the mechanisms of normal development and activation may lead to new therapeutic targets for T cell leukemia and lymphoma. Our studies focus on a novel protein, Shcbp1, which we believe is involved in regulating proliferation during T cell development and during the primary immune response and may be dysregulated in T cell leukemia and lymphoma.
|Buckley, Monica W; Trampont, Paul C; Arandjelovic, Sanja et al. (2015) ShcA regulates late stages of T cell development and peripheral CD4+ T cell numbers. J Immunol 194:1665-76|
|Buckley, Monica W; Arandjelovic, Sanja; Trampont, Paul C et al. (2014) Unexpected phenotype of mice lacking Shcbp1, a protein induced during T cell proliferation. PLoS One 9:e105576|