Burkitt's Lymphoma and Early B Cell Transformation as Paradigms of How Epstein-Barr Virus Overcomes Apoptosis and Ferroptosis.

Epstein-Barr virus (EBV) is a potent oncogenic virus capable of manipulating cell death and cell survival pathways in order to persist in human B cells. Since the discovery of EBV in Burkitt's lymphoma cells in 1964, cell culture has played an important role in uncovering EBV's ability to overcome cell death pathways such as apoptosis and ferroptosis. Whilst apoptosis is a genetically defined and developmentally regulated non-immunogenic cell death program, ferroptosis is a mode of necrotic cell death that is closely linked to amino acid, lipid, redox, energy, selenium, and iron metabolism. Such cell culture studies have not only played a pivotal role in our understanding of the role of EBV in growth transformation and cancer but have also enriched knowledge in the fields of cell death. Artificial in vitro cell culture conditions including (i) oxygen partial pressure, (ii) media composition, (iii) cell density, (iv) cell-, and (v) pH-homo- versus heterogeneity have profound effects on cell growth and responses to death stimuli. In fact, a search for pro-survival genes in Burkitt's lymphoma cells plated at low cell density in FCS-supplemented RPMI 1640 medium had revealed two genes, glutathione peroxidase-4 (GPX4) and ferroptosis-suppressor protein-1 (FSP1), that are now well-known master regulators protecting cells from ferroptosis. Here we review those early fundamental studies and reflect on the subsequent literature that seeks to understand how EBV viral products can modulate cellular pathways during transformation and oncogenesis, reducing the requirement for mutations in cellular genes that are found more commonly in EBV-negative Burkitt's lymphomas.