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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA089194-02
Application #
6514824
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Finerty, John F
Project Start
2001-03-01
Project End
2006-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
2
Fiscal Year
2002
Total Cost
$249,638
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lauenborg, Britt; Christensen, Louise; Ralfkiaer, Ulrik et al. (2015) Malignant T cells express lymphotoxin ? and drive endothelial activation in cutaneous T cell lymphoma. Oncotarget 6:15235-49
Bagdonaite, Ieva; Wandall, Hans H; Litvinov, Ivan V et al. (2015) Ectopic expression of a novel CD22 splice-variant regulates survival and proliferation in malignant T cells from cutaneous T cell lymphoma (CTCL) patients. Oncotarget 6:14374-84
Willerslev-Olsen, Andreas; Litvinov, Ivan V; Fredholm, Simon M et al. (2014) IL-15 and IL-17F are differentially regulated and expressed in mycosis fungoides (MF). Cell Cycle 13:1306-12
Zhang, Qian; Wang, Hong Yi; Wei, Fang et al. (2014) Cutaneous T cell lymphoma expresses immunosuppressive CD80 (B7-1) cell surface protein in a STAT5-dependent manner. J Immunol 192:2913-9
Ralfkiaer, Ulrik; Lindahl, Lise M; Lindal, Lise et al. (2014) MicroRNA expression in early mycosis fungoides is distinctly different from atopic dermatitis and advanced cutaneous T-cell lymphoma. Anticancer Res 34:7207-17
Fredholm, Simon; Gjerdrum, Lise Mette R; Willerslev-Olsen, Andreas et al. (2014) STAT3 activation and infiltration of eosinophil granulocytes in mycosis fungoides. Anticancer Res 34:5277-86
Lee, Seung-Cheol; Marzec, Michal; Liu, Xiaobin et al. (2013) Decreased lactate concentration and glycolytic enzyme expression reflect inhibition of mTOR signal transduction pathway in B-cell lymphoma. NMR Biomed 26:106-14
Willerslev-Olsen, Andreas; Krejsgaard, Thorbjørn; Lindahl, Lise M et al. (2013) Bacterial toxins fuel disease progression in cutaneous T-cell lymphoma. Toxins (Basel) 5:1402-21
Zhang, Qian; Wei, Fang; Wang, Hong Yi et al. (2013) The potent oncogene NPM-ALK mediates malignant transformation of normal human CD4(+) T lymphocytes. Am J Pathol 183:1971-80
Marzec, Michal; Halasa, Krzysztof; Liu, Xiaobin et al. (2013) Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming. J Immunol 191:6200-7

Showing the most recent 10 out of 56 publications