The long-term objective of the work supported by this grant is to define the role of Epstein-Barr virus (EBV) in Burkitt lymphoma (BL), a B-cell tumor that occurs in geographically distinct regions, and which is also associated with immunosuppression as a consequence of HIV infection and AIDS. The underlying hypothesis of this grant is that EBV contributes directly to BL, despite lack of expression of the known viral transforming genes within the tumor cells. This is supported by the observation that the tumorigenic potential of the BL cell line Akata is dependent on EBV infection and at least two viral gene products the EBV small RNAs EBER-1 and EBER-2. The contribution of the EBER RNAs to tumorigenic potential, however, is partial relative to that conferred by EBV infection as a whole, indicating that additional viral genes expressed during infection of BL cells are important. The immediate goals of the proposed work are to define the mechanistic contributions of the EBER RNAs and other EBV gene products to the tumorigenic potential of BL cells and to lymphomagenesis itself.
Three specific aims are proposed.
Under Aim 1, we will identify the cellular targets of the EBER RNAs and define the mechanisms through which they are regulated. We will address two potential mechanisms of EBER function that are suggested by previous experimental observations. The first is that the EBER RNAs function in posttranscriptional gene silencing through direct RNA:RNA interactions with cellular gene RNAs. The second, based on known interactions of the EBERs with components of the cellular translational machinery, is that the EBERs regulate translation of specific cellular mRNAs.
Under Aim 2, we will define the contributions of proteins encoded by the EBV BamHI rightward transcripts (BARTs) to BL-cell tumorigenic potential, and in particular whether any of these proteins are responsible for the enhanced survival conferred upon BL cells by EBV that is attributed to viral-enforced down-regulation of the c-MYC proto-oncoprotein under growth-limiting conditions.
Under Aim 3, we will assess the importance of EBV genes expressed in BL cell lines to actual lymphomagenesis using the murine model of BL, the Emu-myc transgenic mouse, in which expression of the c-myc proto-oncogene, as in BL, is constitutively overexpressed in B lymphocytes. Specifically, we will express the EBV genes within the B cells of these mice to determine whether this accelerates c-Myc-induced lymphomagenesis, and if so, we will identify the genetic and biochemical basis for this contribution to lymphoma.
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