The purpose of this study is to define better the role and understand the mechanisms and consequences of aberrant Jak/STAT signaling in the pathogenesis of cancer by evaluating human T-cell lymphomas. The accumulated experimental evidence indicates that the Jak1/Jak3/STAT3/STAT5 signaling complex associated with the common g chain (gc) shared by several receptors stimulated by cytokines which are critical for activation and maturation of normal T cells: IL-2, -4, -7, -9, -15, and -21, plays a central role in the pathogenesis of a large subset of T-cell lymphomas. Epigenetic silencing of the gene coding for the SHP-1 tyrosine phosphatase, a negative regulator of the cell signaling, contributes to the aberrant, persistent activation of the gc-related Jak/STAT pathways. To accomplish goals of the study we will examine: ? 1. mechanism and functional role of Jak1 and Jak3 activation in the malignant T-cell transformation. We will focus on the putative role of IL-15 and IL-21 in and the relative contribution of Jak1 and Jak3 to the T-cell lymphomagenesis in vitro and of Jak3 in vivo. ? 2. role of STATS, STAT5a and STAT5b in the T-cell transformation by evaluating their relative contributions to the lymphomagenesis. We will focus on the impact of the three STATs on the T-cell lymphoma cell function and gene expression to identify potential effector proteins directly responsible for the malignant cell phenotype. In addition, we will identify the target genes of the STAT3-induced epigenetic gene silencing. ? 3. role of STAT3 in and the mechanisms of the epigenetic silencing of the SHP-1 gene. We will focus on the role of STAT3 and members of the DNA methyltransferase (DNMT) and methyl CpG-binding (MBD) protein families in the DNA methylation of the SHP-1 gene promoter. ? This study should result in a better understanding of the pathogenesis of at least some subtypes of T-cell lymphoma. Furthermore, it may lead to novel therapy(ies) for the lymphoma based on selective inhibition of these elements of the gc-associated Jak/STAT signal transduction pathway that are preferentially utilized and/or abberantly regulated in malignant T cells. Because constant activation of STAT3 and, to lesser degree, of STAT5 has been documented in a large spectrum of malignancies, results of this study may impact on understanding pathogenesis and, ultimately, on treatment of various type of cancer. ? ? ? ? ? ?
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