(m) TOR signaling in EBV-associated lymphomas

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Lymphomas that are associated with the Epstein-Barr virus (EBV) are particularly frequent in patients with HIV/AIDS, organ transplants and other immunodeficiencies. In the HIV infection they represent an AIDS defining condition and typically present as a high grade, high stage malignancy, frequently involving extranodal sites including oral cavity. The EBV-associated lymphomas (EBV-AL) are rather heterogeneous in regard to the extent of expression of the EBV-encoded genes and, consequently, the apparent role EBV plays in their patogenesis. We have found that rapamycin and its derivative RAD [both act by selectively inhibiting a serine/threonine kinase called TOR or m(mammalian)TOR ], profoundly supress at low nanomolar doses the growth of cultured EBV-positive B-cells in vitro and in vivo (M. Majewski et al. 2000, M. Majewski et al., 2003). However, the exact mechanism of action of the TOR inhibitors on the lymphoma cells, the freqquency of TOR inhibitor sensitivity in various types of EBV-AL, and the putative role of EBV in induction of theTOR signaling remain to be elucidated. The studies proposed here will examine the mechanisms of TOR activation and and role of TOR and its, signaling pathwayin the pathogenesis of EBV-AL. Specifically, we will determine the: 1. activation status of the TOR signaling pathways in uncultured, patient-derived lymphoma cells 2. mechanisms of TOR activation in the lymphoma cells 3. role of TOR signaling in cell transformation of the lymphoma cells These studies may result in novel diagnostic and therapeutic approaches to the EBV-associated lymphomas in HIV/AIDS and other patients.