Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is consistently present in primary effusion lymphomas (PELs). The specificity of this association suggests that KSHV plays an important role in the pathobiology of this lymphoid malignancy occurring more frequently in HIV-infected individuals. We were the first to describe this association, and to develop PEL cell lines, which are still the only efficient tool for viral propagation and isolation, and remain an important source of antigen for serologic assays. Our laboratory has also played a pivotol role in the understanding of the clinical, pathologic, and molecular characteristics of PELs. While much has been learned since the identification of KSHV in PELs, our understanding of this disease remains incomplete. We have collected and characterized a significant number of PEL specimens and cell lines, which will be used as a resource to assess the role of KSHV in the pathobiology of primary effusion lymphomas. KSHV contains multiple putative viral oncogenes, as they encode proteins that can affect cellular proliferation and survival. However, which of these are necessary for PEL development and maintenance remains completely unknown. Activation of the transcription factor NFkB is a likely target of KSHV infection, as it is a potent induced of genes involved in he proliferation and survival of lymphocytes, and an important target of the transforming genes of EBV and HLTV1. Our preliminary data indicates that NFkB is constitutively active in PEL cell lines and clinical samples, and its inhibition results in considerably decreased cellular survival. Therefore, we hypothesize that subversion of cellular signaling cascades by KSHV-encoded genes, and in particular activation of NFkB, is critical for KSHV lymphomagenesis. In addition, we hypothesize that among the KSHV-encoded proteins, vFLIP is responsible for most of the NF-kB activity observed in latently infected PEL cells, which will be tested in Specific Aim #1.
Specific Aim #2 is to analyze the activation of the MAP kinase signal transduction pathways in PEL cells. We will determine the consequences of signaling leading to NF-kB and MAP kinase activation in the proliferation, survival, and phenotypic characteristics of PEL cells (Specific Aim #3). These studies should contribute to our understanding of the molecular mechanisms that are critical in KSHV lymphomagenesis and increase our knowledge of the pathobiology of PEL, a highly aggressive and still incurable type of AIDS-related malignancy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068939-10
Application #
6856549
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (08))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1995-07-06
Project End
2008-02-28
Budget Start
2005-03-01
Budget End
2008-02-28
Support Year
10
Fiscal Year
2005
Total Cost
$276,073
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
Nayar, Utthara; Lu, Pin; Goldstein, Rebecca L et al. (2013) Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies. Blood 122:2837-47
Giulino-Roth, Lisa; Wang, Kai; MacDonald, Theresa Y et al. (2012) Targeted genomic sequencing of pediatric Burkitt lymphoma identifies recurrent alterations in antiapoptotic and chromatin-remodeling genes. Blood 120:5181-4
Giulino, Lisa; Mathew, Susan; Ballon, Gianna et al. (2011) A20 (TNFAIP3) genetic alterations in EBV-associated AIDS-related lymphoma. Blood 117:4852-4
Cesarman, Ethel (2011) Gammaherpesvirus and lymphoproliferative disorders in immunocompromised patients. Cancer Lett 305:163-74
Sun, Shao-Cong; Cesarman, Ethel (2011) NF-?B as a target for oncogenic viruses. Curr Top Microbiol Immunol 349:197-244
Ballon, Gianna; Chen, Kang; Perez, Rocio et al. (2011) Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice. J Clin Invest 121:1141-53
Carbone, Antonino; Cesarman, Ethel; Gloghini, Annunziata et al. (2010) Understanding pathogenetic aspects and clinical presentation of primary effusion lymphoma through its derived cell lines. AIDS 24:479-90
Di Bartolo, Daniel L; Hyjek, Elizabeth; Keller, Shannon et al. (2009) Role of defective Oct-2 and OCA-B expression in immunoglobulin production and Kaposi's sarcoma-associated herpesvirus lytic reactivation in primary effusion lymphoma. J Virol 83:4308-15
Guasparri, Ilaria; Bubman, Darya; Cesarman, Ethel (2008) EBV LMP2A affects LMP1-mediated NF-kappaB signaling and survival of lymphoma cells by regulating TRAF2 expression. Blood 111:3813-20
Czuchlewski, David R; Csernus, Balazs; Bubman, Darya et al. (2008) Expression of the follicular lymphoma variant translocation 1 gene in diffuse large B-cell lymphoma correlates with subtype and clinical outcome. Am J Clin Pathol 130:957-62

Showing the most recent 10 out of 13 publications