The purpose of this study is to define the role and understand the mechanisms of aberrant cytokine signaling in the pathogenesis and progression of human cutaneous T-cell lymphoma (CTCL). It will focus on the role in CTCL of the Jak/STAT signaling pathway associated with the cytokine receptor common y chain (yc) shared by several receptor stimulated by cytokines which are critical for activation and maturation of normal T cells: lL-2, -4, -7, -9, and -15. Our preliminary data indicate that the yc-associated Jak/STAT pathway is activated in CTCL cells. Whereas in the less advanced (low grade/low stage) cases of CTCL this activation appears cytokine induced, in the more advanced (intermediate/high grade/high stage) cases it is constitutive and at least in part due to the lack of negative regulation normally mediated by a SHP-1 phosphatase. In this study we will examine in detail the expression, functional status, and role in malignant cell transformation of the Jak/STAT signal transduction pathway as well as inhibitors of this pathway (SHP-1 phosphatase and PIAS and SOCS proteins) using cultured and fresh CTCL cells. Particular attention will be paid to the differences in functioning of the Jak/STAT pathway between the indolent (low grade/low stage) and aggressive (intermediate/high grade/high stage) types of CTCL. In the indolent CTCL, experiments will be performed to determine which of the yc-signaling cytokines is (are) critical for growth and survival of the malignant T cells.
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