Burkitt lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL in developing countries, necessitating new strategies. We used high throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways that cooperate with MYC, the defining oncogene of this cancer. In 38% of sporadic BL (sBL) cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. In 70% of sBL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival PI(3) kinase pathway in BL, in part by augmenting constitutive B cell receptor signaling. These findings suggest opportunities to improve therapy for patients with BL.

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Recently established Epstein‐Barr virus (EBV)‐positive Burkitt's lymphoma (BL) cell lines, carrying chromosomal translocations indicative of their malignant origin, have been monitored for their degree of in vitro progression towards a more ‘lymphoblastoid’ cell surface phenotype and growth pattern, and for their expression of three EBV latent gene products which are constitutively present in all virus‐transformed normal lymphoblastoid cell lines (LCLs). BL cell lines which stably retained the original tumour biopsy phenotype on serial passage were all positive for the nuclear antigen EBNA 1 but did not express detectable amounts of two other ‘transforming’ proteins, EBNA 2 and the latent membrane protein (LMP). This novel pattern of EBV gene expression was also observed on direct analysis of BL biopsy tissue. All three viral proteins became detectable, however, in BL cell lines which had progressed towards a more LCL‐like phenotype in vitro. This work establishes a link between B cell phenotype and the accompanying pattern of EBV latent gene expression, and identifies a novel type of EBV:cell interaction which may be unique to BL cells.

(6) strongly supported this latter possibility. Thus EBV-positive Burkitt lymphoma (BL) cell lines displaying the latency I form of infection, in which only the nuclear antigen EBNAl is expressed, could readily be induced into apoptosis by signals such as serum withdrawal or treatment with calcium ionophore (5). In contrast BL lines that had progressed on serial passage to a latency III form of infection, with expression of the full spectrum of latent proteins, including nuclear antigens EBNAs 1, 2, 3A, 3B, 3C, and LP and the latent membrane proteins (LMPs) 1 and 2, showed enhanced cell survival under such conditions. Gene transfers into apoptosis-sensitive B-cell lines mapped this protective effect to LMP1 and indicated a likely mechanism, namely, LMPl-mediated up-regulation of the cellular protein Bcl-2 (7). Importantly Bcl-2, a membrane-associated protein with a distinctive pattern of cytoplasmic localization (8, 9), not only enhances cell survival in a variety of experimental situations (7, 9-15) but also appears to be involved in the physiological selection of B cells into memory (16 (Fig. 1).Transfections. Transient transfections into COS-1 cells using DEAE-dextran and stable transfections into the EBVpositive BL cell lines Wan-BL (23), Akata-BL (24), and Raji-BL (25) by using electroporation were performed as described (7,26). For the latter, selection was in hygromycin B at 300 ug/ml (pHEBO-based constructs) or G418 at 2.5 mg/ml ref. 27