Tsc1/mTOR axis in immune homeostasis and tumorigenesis

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DESCRIPTION (provided by applicant): Aberrant activation of mTOR, a central regulator of cell growth and metabolism, is a common molecular event in a number of human malignancies including T-lymphoblastic leukemia (T-ALL), a hematological cancer with poor prognosis. Emerging evidence also highlights a crucial role of mTOR signaling in T cell activation and differentiation. The requirement of mTOR for T cell responses is reflective of the unique feature of T cell activation, in that actively cycling T cells undergo massive clonal expansion with a rate of proliferation (doubling every 5-6 hours) exceeding that of any other cells in the adult mammalian system. Concomitant with T cell activation is the reprogramming of the metabolic machinery. Conversely, in the absence of antigen stimulation, T cells exist in a state known as quiescence defined by a small cell size and exit from the cell cycle. Quiescence has been suggested to reduce the energy and space required to maintain a large repertoire of lymphocytes, but how it is regulated remains poorly defined. We recently identified that Tsc1 enforces T cell quiescence by actively controlling mTOR activity. We hypothesize that Tsc1 and mTOR signaling orchestrates a metabolic checkpoint for naive T cell quiescence, and loss of this control mechanism exacerbates leukemia genesis via metabolic dysregulation and inflammatory pathways. We will test this hypothesis by establishing the metabolic and signaling mechanisms in Tsc1-dependent regulation of T cell quiescence, and determining how these Tsc1-mediated effector pathways contribute to the development of leukemia in murine models and human T-ALL. We predict our studies will establish a new paradigm on our understanding of T cell quiescence by linking this process to metabolic pathways for the first time, and by establishing the functional significance of quiescence enforcement on leukemogenesis and tumor-related inflammation. Insights gained from this project will likely lead to the identificatio of innovative strategies (e.g. targeting metabolic and inflammatory pathways, in addition to inhibiting mTOR) for leukemia intervention.