Preventing Cks1-mediated p27 Degradation Delays LMP2A/MYC-driven Lymphomagenesis

Epstein-Barr virus (EBV) is a Υ-herpesvirus that establishes latent infection in over 90% of adults. Latent EBV infection in B cells is associated with several types of cancer, including Burkitt’s lymphoma. Latent membrane protein 2A (LMP2A) is an EBV-encoded protein that is expressed during latency and has been detected in Burkitt’s lymphoma. Tumors isolated from an LMP2A/MYC transgenic mouse model of Burkitt’s lymphoma displayed diminished levels of p27, which prevents cell cycle progression from G1 to S phase. MYC mice homozygously expressing a S10A mutant form of p27 (p27S10A/S10A) show a significant increase in tumor-free survival. Cell cycle progression from G1 to S phase in pre-tumor, splenic B-cells is also decreased. In the LMP2A/-MYC model, however, no such effects are observed. The S10A mutation localizes p27 to the nucleus, preventing its cytoplasmic degradation. Nuclear degradation of p27 is mediated by the SCFSkp2 complex. A major component of this complex is Cks1, which recognizes p27 and recruits it for ubiquitination and subsequent degradation. We hypothesize that interfering with nuclear export and Cks1-mediated nuclear degradation of p27 can prevent LMP2A/MYC-driven lymphomagenesis in vivo. Our results show that LMP2A/MYC mice homozygously expressing the S10A mutant of p27 combined with a homozygous Cks1 knockout display a delayed tumor onset, increased p27 levels and G1 cell cycle arrest, and decreased splenomegaly. In future studies, we will attempt to duplicate these effects using a Cdk4/6 inhibitor, to determine whether this may be used as a potential treatment for EBV-associated Burkitt's lymphoma.