Latent Membrane Proteins from EBV Differentially Target Cellular Pathways to Accelerate MYC-induced Lymphomagenesis

Blood Adv. 2022 May 23;bloodadvances.2022007695. doi: 10.1182/bloodadvances.2022007695. Online ahead of print.

Abstract

MYC translocations in association with Epstein-Barr virus (EBV) infection are often observed in B-cell lymphomas. A subset of Burkitt lymphoma (BL) express EBV latent membrane protein 1 and 2A (LMP1 and LMP2A) in addition to the typical restricted EBV latent gene expression. EBV-associated DLBCL typically exhibit latency type II or III and express LMP1. Here, we investigate the role of LMP1 in MYC-driven lymphomagenesis in our murine model. λ-MYC mice develop tumors having a "starry-sky" appearance and have abnormal p53 expression that is also observed in human BL. LMP2A/λ-MYC double-transgenic mice develop tumors significantly faster than mice only expressing MYC. Similar to LMP2A/λ-MYC mice, LMP1/λ-MYC mice also have accelerated MYC-driven lymphomagenesis. As observed in LMP2A/λ-MYC mice, p27kip1 was degraded in LMP1/λ-MYC pretumor and tumor B cells. Coexpression of LMP1 and LMP2A resulted in enhancement of B cell proliferation. In contrast to LMP2A, the inhibition of Syk or CDK4/6 activity did not effectively inhibit LMP1-mediated MYC lymphomagenesis. Also in contrast to LMP2A, LMP1 did not lessen abnormal p53 expression in λ-MYC tumors. To investigate the significance of LMP1 expression in human BL development, we reanalyzed 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 LMP1 effects in EBV-associated human BL varies from what we observe in our murine model. Finally our studies suggest a novel pathogenic role of LMP1 in lymphomagenesis.