LMP2A-The Other EBV Oncogene.

Abstract

LMP2A is the Rodney Dangerfield of viral oncogenes: It gets no respect. Initial impressions-that it was dispensable for EBV transformation of B lymphocytes and only enhanced transformation efficiency-still shape how this oncogene is viewed. This view needs to be reconsidered in light of a wealth of evidence supporting its role as a key oncogene in EBV-associated malignancies. LMP2A constitutively activates the PI3K/Akt/mTOR pathway, the most frequently mutated pathway in human cancer. In nasopharyngeal and gastric carcinomas, which account for most EBV-associated cancers, LMP2A is expressed much more frequently than LMP1 and is a dependency factor in both malignancies. Additionally, as a B cell receptor (BCR) mimic, LMP2A plays an essential role in EBV's persistence strategy of establishing life-long infection in memory-like B cells by mimicking germinal center reactions and maintaining EBV latency. Finally, recent studies suggest that LCLs are dependent on LMP2A signaling and ΔLMP2A-LCLs are phenotypically distinct from wildtype LCLs. As we seek to define EBV's role in autoimmunity, it will be important to understand the extent to which LMP2A contributes to these diseases as well. As a constitutive BCR mimic, LMP2A may drive aberrant B cell activation and survival, potentially promoting the breakdown of tolerance. We should be cautious not to underestimate its role in autoimmunity as was once done in cancer.