Epstein-Barr Virus Induced B cell Methionine Dependency is a Targetable Metabolic Vulnerability

Isotope-labeled amino acid tracing indicated that methionine was shunt to cysteine biosynthesis pathway. Methionine restriction can be rescued by a combination of quenching LPO (Fer-1 and DFO) and removing toxic cystine buildup (NAC and penicillamine). In mice models, either dietary methionine restriction or injection of engineered methioninase abolished lymphoblastoid cell line tumor growth without having effects on body weight, and refractory tumor cells upregulated pathways against LPO, and downregulated cystine intake, highlighting methionine’s multiple roles in antagonizing LPO and redox pressure via modulating cysteine metabolism.

In tonsil organoid model, moderate methionine restriction blocks EBV+ cell outgrowth but did not affect T cell activation and normal germinal center development, implying therapeutic potential. In a B cell transformation assay with a panel of loss-of-function BAC viruses, we identify EBNA2, EBNA-LP, and LMP2A deletion provided protection.