Two Pathways of p27 Degradation Are Required for Murine Lymphoma Driven by Myc and EBV Latent Membrane Protein 2A.

Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A), expressed in EBV latency, contributes to Burkitt lymphoma (BL) development in a murine model by acting as a constitutively active B cell receptor (BCR) mimic. Mice expressing both LMP2A and transgenes (LMP2A/λ-) develop tumors significantly faster than mice only expressing (λ-). Previously, we demonstrated the cell cycle inhibitor p27 is present at significantly lower levels in LMP2A/λ- mice due to increased posttranslational degradation. P27 degradation can occur in the cytoplasm following phosphorylation on serine 10 (S10) or in the nucleus via the SCF complex, which depends on Cks1. We previously demonstrated an S10A knock-in of p27 (p27) that prevented S10 phosphorylation failed to significantly delay tumor onset in LMP2A/λ- mice. We also previously demonstrated that a knockout partially delayed tumor onset in LMP2A/λ- mice, but onset was still significantly faster than that in λ- mice. Here, we have combined both genetic manipulations in what we call p27 mice. LMP2A/λ-/p27 mice and λ-/p27 mice both displayed dramatic delays in tumor onset. Strikingly, tumor development in LMP2A/λ-/p27 mice was later than that in λ- mice and not significantly different from that in λ-/p27 mice. The p27 genotype also normalized G-S-phase cell cycle progression, spleen size, and splenic architecture in LMP2A/λ- mice. Our results reveal both major pathways of p27 degradation are required for the accelerated BL development driven by LMP2A in our BL model and that blocking both degradation pathways is sufficient to delay Myc-driven tumor development with or without LMP2A. BL is a cancer that primarily affects children. The side effects of chemotherapy highlight the need for better BL treatments. Many BL tumors contain EBV, and our goal is to determine what makes EBV-positive BL different from EBV-negative BL. This may lead to more specific treatments for both types. All cases of BL require overexpression of Mice engineered to express EBV LMP2A along with (LMP2A/λ- mice) develop tumors much more quickly than mice only expressing (λ- mice). Blocking degradation of the cell cycle inhibitor protein p27 in LMP2A/λ- mice causes tumors to develop later than in λ- mice, showing that p27 degradation may play a larger role in EBV-positive BL than EBV-negative BL. Furthermore, our studies suggest the cell cycle is an attractive target as a treatment option for LMP2A-positive cancers in humans.