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

Masato Ikeda*, Cooper K. Hayes, Samantha J. Schaller, Richard Longnecker

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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. l-MYC mice develop tumors having a “starry sky” appearance and have abnormal p53 expression that is also observed in human BL. LMP2A/l-MYC double-transgenic mice develop tumors significantly faster than mice only expressing MYC. Similar to LMP2A/l-MYC mice, LMP1/l-MYC mice also have accelerated MYC-driven lymphomagenesis. As observed in LMP2A/l-MYC mice, p27kip1 was degraded in LMP1/l-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 l-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.

Original languageEnglish (US)
Pages (from-to)4283-4296
Number of pages14
JournalBlood Advances
Volume6
Issue number14
DOIs
StatePublished - Jul 26 2022

ASJC Scopus subject areas

  • Hematology

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