EBV infects approximately 95% of the human population resulting in a benign, lifetime latent infection of B lymphocytes. EBV is unique in that latent infection can lead to virus-associated malignancies such as Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL). These EBV-associated malignancies occur with high incidence in HIV/AIDS patients resulting in serious complications. Research in our laboratory has concentrated on understanding EBV latent infection and the resulting pathologies so that targeted therapies can be developed. Latent membrane protein 2A (LMP2A) is an EBV protein expressed in latently infected B-lymphocytes and detected in all EBV-associated malignancies including those seen in HIV/AIDS patients. LMP2A mimics normal B cell signaling pathways induced by the B cell receptor (BCR) and prevents apoptosis and prolongs cell survival. We have shown that LMP2A function is dependent on numerous cellular proteins including the cellular signal transducers Lyn, Syk, Abl, Akt, mTOR, Btk, BLNK, PI3-Kinase, and Ras. In our most recent studies, we have shown that LMP2A reduces the levels of p27, an important tumor suppressor that regulates the cell cycle. We also found that LMP2A simultaneously amplifies Myc expression. Thus, LMP2A provides two key hallmarks associated with the conversion of a normal cell to a cancer cell - prevention of apoptosis and activation of the cell cycle. In the current proposal, we plan to investigate the mechanism of p27 degradation and to identify the LMP2A activated proteins that target p27 for degradation using pharmacological inhibitors of LMP2A activated proteins. Ultimately, our studies may result in the development of novel treatments for EBV-related lymphoproliferative diseases that occur in HIV/AIDS patients, how these inhibitors work, and a better understanding of EBV latent infection in humans.

Public Health Relevance

Our specific aims are to identify cellular and viral factors that are important for Epstein-Barr virus (EBV) latent infections and EBV-associated hematological cancers and proliferative disorders that occur in the human host and those in particular that occur in HIV/AIDS patients. An understanding of how EBV contributes to EBV lymphoproliferative disease and other EBV-related pathologies in HIV/AIDS patients may provide insight for the development of novel therapeutics for the treatment or eradication of EBV-associated disease in HIV/AIDS patients, the ultimate goal of our studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA073507-16
Application #
8789112
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Daschner, Phillip J
Project Start
1997-02-01
Project End
2019-05-31
Budget Start
2014-07-01
Budget End
2015-05-31
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60611
Fish, Kamonwan; Chen, Jia; Longnecker, Richard (2014) Epstein-Barr virus latent membrane protein 2A enhances MYC-driven cell cycle progression in a mouse model of B lymphoma. Blood 123:530-40
Bragelmann, J; Dagogo-Jack, I; El Dinali, M et al. (2013) Oral cavity tumors in younger patients show a poor prognosis and do not contain viral RNA. Oral Oncol 49:525-33
Shim, Ann Hye-Ryong; Chang, Rhoda Ahn; Chen, Xiaoyan et al. (2012) Multipronged attenuation of macrophage-colony stimulating factor signaling by Epstein-Barr virus BARF1. Proc Natl Acad Sci U S A 109:12962-7
Vrazo, Alexandra C; Chauchard, Maria; Raab-Traub, Nancy et al. (2012) Epstein-Barr virus LMP2A reduces hyperactivation induced by LMP1 to restore normal B cell phenotype in transgenic mice. PLoS Pathog 8:e1002662
Chang, Rhoda A; Miller, Stephen D; Longnecker, Richard (2012) Epstein-Barr virus latent membrane protein 2A exacerbates experimental autoimmune encephalomyelitis and enhances antigen presentation function. Sci Rep 2:353
Dargart, Jamie L; Fish, Kamonwan; Gordon, Leo I et al. (2012) Dasatinib therapy results in decreased B cell proliferation, splenomegaly, and tumor growth in a murine model of lymphoma expressing Myc and Epstein-Barr virus LMP2A. Antiviral Res 95:49-56
Cen, Osman; Longnecker, Richard (2011) Rapamycin reverses splenomegaly and inhibits tumor development in a transgenic model of Epstein-Barr virus-related Burkitt's lymphoma. Mol Cancer Ther 10:679-86
Bieging, Kathryn T; Fish, Kamonwan; Bondada, Subbarao et al. (2011) A shared gene expression signature in mouse models of EBV-associated and non-EBV-associated Burkitt lymphoma. Blood 118:6849-59
Bieging, Kathryn T; Swanson-Mungerson, Michelle; Amick, Alexandra C et al. (2010) Epstein-Barr virus in Burkitt's lymphoma: a role for latent membrane protein 2A. Cell Cycle 9:901-8
Swanson-Mungerson, Michelle; Bultema, Rebecca; Longnecker, Richard (2010) Epstein-Barr virus LMP2A imposes sensitivity to apoptosis. J Gen Virol 91:2197-202

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