This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tumors inhibit T cell proliferation through several mechanisms, including the depletion of the non-essential amino acid L-Arginine (L-Arg) by arginase I produced in myeloid derived suppressor cells (MDSC). Our preliminary data show that L-Arg depletion by arginase I impairs primary T cell proliferation and found that it specifically inhibits the expression of cyclin D3, arresting T cells in G0-G1 phase of the cell cycle. We therefore propose that arginase may also be an important therapeutic agent in T cell malignancies. In this proposal we will study the mechanisms by which L-Arg starvation impairs proliferation of malignant T cells and test whether arginase injection can be used in vivo for the treatment of T cell leukemias. Our hypothesis is that L-Arg starvation by arginase I blocks malignant T cell proliferation by inhibiting the expression of cell cycle associated proteins and can therefore be used in the treatment of T cell proliferate disorders such as T cell leukemia. To test this hypothesis, we propose the following specific aims: 1. To characterize the molecular mechanisms by which L-Arginine starvation impairs malignant T cell proliferation in vitro. 2. To test the prediction that arginase I injection will decrease L-Arginine levels and block cyclin D3 expression in vivo in a T cell leukemia model. 3. To determine whether GCN2 kinase activation in malignant T cells is the major check point that initiates the post-transcriptional and translational changes induced by L-Arginine starvation. 4. To test whether therapies targeting GCN2 pathway induce an anti-tumoral effect in T cell malignancies. 5. Test the prediction that arginase treatment induces an anti-tumoral effect in samples from T-ALL patients injected into immunodeficient mice.
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