L-ARGININE AVAILABILITY REGULATES PROLIFERATION OF MALIGNANT T-CELLS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. T cell malignancies have a poor prognosis, especially in adult patients. Therefore new therapies that result in increased response and survival of the patients are urgently needed. We previously demonstrated that Arginase 1 produced by inflammatory cells in solid tumors, arrests the proliferation of normal T cells by depleting L-Arginine and blocking specific pathways. Interestingly, Arginase 1 production is not found in patients with T cell leukemias. We therefore tested whether Arginase 1 would also inhibit T cell leukemia proliferation. Our preliminary results show that malignant T cells require high concentrations L-Arginine (L-Arg) to sustain their high rate of proliferation. In vitro depletion of L-Arg by Arginase I blocks malignant T cell proliferation, and arrests malignant T cells in the G0-G1 phase of the cell cycle by impairing the expression of cyclin D3. We also identified some of the molecular mechanisms involved in this process. The decrease in cyclin D3 protein expression was caused by post-transcriptional mechanisms including a decreased cyclin D3 mRNA stability and an arrest in cyclin D3 translation. The loss of cyclin D3 mRNA half-life induced by the absence of L-Arg was mediated by sequences within the 3'-untranslated region (3'-UTR) of the cyclin D3 mRNA and associated with a low in vitro binding of the RNA-binding protein HuR. Furthermore, the decreased translation of cyclin D3 in the absence of L-Arg correlated with the activation of the amino acid starvation sensor GCN2 kinase. These results support the hypothesis that L-Arg starvation by arginase I blocks malignant T cell proliferation by blocking specific pathways including the expression of cyclin D3. Arginase I can therefore be used in the treatment of T cell lympho-proliferative disorders such as T-ALL. In this study, we propose to identify the molecular mechanisms by which L-Arg depletion impairs malignant T cell proliferation and determine if L-Arg depletion by the injection of Arginase I, or targeting pathways triggered by L-Arg starvation, can be used as a new treatment in T cell leukemias. The initial murine model results demonstrate that the injection of pegylated arginase I (peg-Arg I) prolongs survival in mice bearing T-ALL tumors. Information garnered from this effort may lead to the development of a novel and important therapeutic approach to complement existing therapies for T cell lympho-proliferative disorders such as T-ALL.