""""""""The work of the Lymphoma Biology Section is ultimately directed towards the development of improved therapy for the treatment of lymphoid malignancies in children and young adults, with special emphasis on Burkitt's lymphoma (BL). A major goal is to better elucidate the nature and consequences of the genetic changes that lead to lymphoid neoplasia, based on the hypothesis that such information will lead to improved diagnostic tools, the identification of prognostic factors of value in patient stratification for therapy, and the identification of molecular targets for novel therapeutic endeavors. We have also attempted to identify molecular differences in different age groups, different geographic regions, and in tumors arising in normal versus immunosuppressed hosts. Our clinical protocols have sought to take advantage of unique opportunities at the NCI to explore, in pilot studies, the hypotheses that 1) adults with BL or BL-like lymphomas require therapy similar to the effective protocols used in children, and 2) the lives of children with HIV-associated lymphomas can be significantly prolonged by judiciously designed chemotherapy. The first hypothesis appears to be valid in the completed pilot protocol (in all, 116 patients were accrued on study), in which an overall event free survival (EFS) rate in 91 patients with B cell lymphomas is 88%, with no survival difference between children and adults. Even patients with the most extensive disease (bone marrow and CNS involvement) achieved an EFS rate of close to 80%. This protocol is now being further explored by the UK NLI Cooperative Group. We have also studied late effects in patients treated in the Pediatric Oncology Branch since 1974. The small study for immunosuppressed patients has been successful in preventing patients from dying from lymphoma or its treatment. Our studies of pathogenetic mechanisms were focused, in the past, on the c-myc gene, (deregulated by the 8;14 translocation in BL), and on Epstein Barr virus. More recently they have been expanded to include a number of additional genes. For example, we have demonstrated that the functional loss of the cdk inhibitor, p16 is almost universal in BL. We have also studied the mechanisms whereby BL cells escape apoptosis and shown that in most BL cell lines the Fas apoptotic pathway is inactivated by at least two different mechanisms. One of these, surprisingly, involves inactivation of the pro-apoptotic protein, Bax, and we have gone on to demonstrate that Bax interacts with an early component of the Fas pathway. Our studies with EBV have been primarily directed towards EBNA-1, the only EBV gene expressed in BL. We have identified sequence changes in EBNA-1 that demonstrate body compartment and tumor specificity. Interestingly, the commonest EBNA-1 subtype in normal lymphocytes (P-ala) appears to be incompatible with lymphomagenesis while the spectrum of EBNA-1 subtypes differs in BL and nasopharyngeal carcinoma (NPC). Nasal lymphomas, however, unlike BL and NPC, contain mixtures of EBNA-1 subtypes with incremental accumulation of mutations, strongly suggesting that EBNA-1 mutations arise in vivo. We have identified two separate regions of EBNA-1 capable of independent transactivation and have also identified a cellular protein, p32/TAP, that binds EBNA-1. Our early studies suggest that this protein appears to be involved in the ability of EBNA-1 to transactivate. Finally, we have used EBNA-1 as a therapeutic target, and shown specific killing of BL cells in vitro using EBNA-1 to drive a pro-drug activating enzyme, or the Zta gene of EBV. Zta expression causes cell death via activation of the viral lytic cycle; thus both levels of specificity in this system are EBV-dependent. HIV associated work, 10%.""""""""
