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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA089194-09
Application #
7667221
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Howcroft, Thomas K
Project Start
2001-03-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
9
Fiscal Year
2009
Total Cost
$249,891
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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