Two pathways of p27Kip1 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 MYC transgenes (LMP2A/l-MYC) develop tumors significantly faster than mice only expressing MYC (l-MYC). Previously, we demonstrated the cell cycle inhibitor p27 Kip1 is present at significantly lower levels in LMP2A/l-MYC mice due to increased post-translational degradation. P27 Kip1 degradation can occur in the cytoplasm following phosphorylation on serine 10 (S10), or in the nucleus via the SCF Skp2 complex, which depends on Cks1. We previously demonstrated a S10A knock-in of p27 Kip1 (p27 S10A/S10A ), which prevented S10 phosphorylation, failed to significantly delay tumor onset in LMP2A/l-MYC mice. We also previously demonstrated that a Cks1 knockout partially delayed tumor onset in LMP2A/l-MYC mice, but onset was still significantly faster than in l-MYC mice. Here, we have combined both genetic manipulations in what we call p27 Super mice. LMP2A/l-MYC/p27 Super mice and l-MYC/p27 Super mice both displayed dramatic delays in tumor onset. Strikingly, tumor development in LMP2A/l-MYC/p27 Super mice was later than in l-MYC mice and not significantly different from l-MYC/p27 Super mice. The p27 Super genotype also normalized G 1 -S phase cell cycle progression, spleen size, and splenic architecture in LMP2A/l-MYC mice. Our results reveal both major pathways of p27 Kip1 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.