Latent membrane proteins from EBV differentially target cellular pathways to accelerate MYC-induced lymphomagenesis

MYC translocations in association with Epstein-Barr virus (EBV) infection are often observed in B-cell lymphomas. A subset of Burkitt lymphoma (BL) expresses EBV latent membrane proteins 1 and 2A (LMP1 and LMP2A) in addition to the typical restricted EBV latent gene expression. EBV-associated diffuse large B-cell lymphoma (DLBCL) typically exhibits latency type II or III and expresses LMP1. Here, we investigate the role of LMP1 in MYC-driven lymphomagenesis in our murine model. lambda-MYC mice develop tumors having a starry sky appearance and have abnormal p53 expression that is also observed in human BL. LMP2A/lambda-MYC double-transgenic mice develop tumors significantly faster than mice only expressing MYC. Similar to LMP2A/lambda-MYC mice, LMP1/lambda-MYC mice also have accelerated MYC-driven lymphomagenesis. As observed in LMP2A/lambda-MYC mice, p27(kip1) was degraded in LMP1/lambda-MYC pretumor and tumor B cells. Coexpression of LMP1 and LMP2A resulted in the enhancement of B cell proliferation. In contrast to LMP2A, the inhibition of Syk or cyclin-dependant kinase (CDK)4/6 activity did not effectively inhibit LMP1-mediated MYC lymphomagenesis. Also, in contrast to LMP2A, LMP1 did not lessen abnormal p53 expression in lambda-MYC tumors. To investigate the significance of LMP1 expression in human BL development, we reanalyzed RNA sequencing (RNA-Seq) data of primary human BL from previous studies. Interestingly, p53 mutations were less observed in LMP1-expressing BL, although they were not significantly changed by EBV infection, indicating LMP1 may lessen p53 mutations in human primary BL. This suggests that LMP1 effects in EBV-associated human BL vary from what we observe in our murine model. Finally, our studies suggest a novel pathogenic role of LMP1 in lymphomagenesis.

Automated summary

The study reveals the significant role of LMP1 in MYC-driven lymphomagenesis, and suggests that it may lessen p53 mutations in human BL.