KSHV/HHV-8 is clearly etiologically associated with Kaposi's sarcoma. This virus can be found in the B cells of infected individuals, both in the circulation and mantle zones of lymph nodes. In addition it is present in B cells in a large proportion of multicentric Castleman's disease as well as in B cell lymphomas, specifically primary effusion lymphomas (PEL) and a subset of large cell non-Hodgkin's lymphomas in HIV-positive individuals not involving body cavities. While KSHV-infection is not sufficient for the development of these disorders, the specific association suggests that KSHV plays a role in their pathogenesis. We hypothesize that that vFLIP is a critical mediator of this oncogenic consequence of viral infection. In support of this hypothesis our preliminary data indicates that vFLIP activates NF-KappaB in B cells, that NF-KappaB activity is essential for the survival of PEL cells, and that vFLIP is largely responsible for the constitutive NF-KB activity seen in latently infected lymphoma cells. We propose that vFLIP protects cells from apoptosis by a two pronged effect on TNF-signaling pathways: first directly by interfering with the activation and function of the death-inducing signaling complex (DISC), and second indirectly by forming a life-inducing signaling complex (LISC) which leads to NF-KappaB activation, in turn inducing expression of anti-apoptotic genes. We will test this model and determine the role of vFLIP in the survival of B cells through the following specific aims: 1) Characterize the role of vFLIP in PEL cell survival; 2) Perform a structural and functional characterization of vFLIP activity in B cells; and 3) Assess vFLIP function in vivo. These studies will lead to a detailed understanding of the contribution of KSHV vFLIP to the survival of infected B cells and lymphomagenesis, and validate vFLIP as a therapeutic target for the treatment of primary effusion lymphoma and perhaps other KSHV-associated diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA103646-03
Application #
7055278
Study Section
Special Emphasis Panel (ZRG1-AARR-B (03))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2004-05-01
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
3
Fiscal Year
2006
Total Cost
$336,307
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pathology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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Nayar, Utthara; Lu, Pin; Goldstein, Rebecca L et al. (2013) Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies. Blood 122:2837-47

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