The purpose of this study is to investigate the role of cytokine mediated signal transduction pathway in the pathogenesis of human lymphomas. Specifically, the study will focus on the role of signals mediated through receptor for interleukin-2 (IL-2R) in the malignant transformation of T lymphocytes. Part of the IL-2R, common gamma chain (gamma c) is shared by receptors for several cytokines: IL-2, IL-4, IL-7, IL-9, and IL-15. Expression of the gamma c chain is essential for development and proliferation of normal T lymphocytes. In this study they will explore the expression, function and molecular structure of the gamma c and the cytokine-specific receptors which associate with gamma c by various types of malignant T-cell lymphoma. They will also examine whether the cytokines which signal through the cytokine receptors containing gamma c are synthesized and utilized by the malignant cells. Furthermore, they will study the expression, functional status, and structure of the IL-2R associated Jak/STAT signal transduction pathway as well as various, novel inhibitors of this pathway (members of the cytokine-receptor binding phosphatase, CIS/SOCS/SSI, and PIAS protein families). Finally, the expression, function, and structure of other molecles activated by IL-2R such as P13K, AKT, and STAM will also be determined. Particular attention will be paid to the possible differences in the IL-2R signaling between the indolent (low-grade/low stage) and aggressive (intermediate/high- grading/high state) variants of T-cell lymphoma. This study may result in a better understanding of the pathogenesis of at least some types of T-cell lymphoma. Consequently, it may lead to novel therapies for lymphoma based on selective inhibition of these elements of IL-2R signal transduction pathway(s) which are utilized by malignant T-cells.
