(A) In the λ-MYC mouse model, MYC is expressed from an immunoglobulin promoter in B cells. Expression of deregulated MYC activates the p53 pathway, triggering apoptosis. Burkitt’s lymphoma-like tumors are eventually observed in these mice upon mutation or inactivation of one or more components of the p53 pathway. (B) Both LMP2A and MYC are expressed in B cells throughout development in the LMP2A/λ-MYC transgenic mouse. The MYC transgene activates the p53 pathway, but LMP2A counteracts this activation, likely at some step that is downstream of PUMA, possibly through upregulation of anti-apoptotic proteins. LMP2A causes an initial expansion of cells, observed as splenomegaly in pre-tumor animals. In the absence of immune selection, LMP2A accelerates tumor onset in this model, allowing tumorigenesis in the presence of an intact p53 pathway.

Deregulation of MYC causes mitogentic signals that trigger ARF. ARF inhibits MDM2, a ubiquitin ligase that targets p53 for protein degradation. Nutlin 3 is an inhibitor that blocks the interaction between MDM2 and p53, leading to activation of p53 and downstream effectors. Activated p53 can bind DNA and induce expression of pro-apoptotic proteins, including PUMA, NOXA, and BAX. In addition, p53 transcriptionally upregulates MDM2, and inhibits ARF, mechanisms that downregulate the p53 response. PUMA, NOXA, and BIM are pro apoptotic BH-3 only proteins that can directly bind to pro-survival Bcl-2 family members, such as Bcl-2, Bcl-X_L, and Mcl-1. Pro-survival Bcl family members prevent insertion of BAX into the mitochondrial membrane. BAX insertion triggers release of cytochrome c from the mitochondria, leading to activation of downstream caspases and, ultimately, apoptosis.

(A) In EBV-negative human BL, translocation of MYC to an immunoglobulin locus occurs during a germinal center reaction. MYC induces p53 pathway activation, triggering apoptosis. Cells which have inactivated the p53 pathway grow into lymphoma. (B) In EBV-positive human BL, LMP2A is present during the germinal center reaction and MYC translocation. LMP2A enhances the survival of cells with de-regulated MYC early in lymphomagenesis, allowing expansion of cells that overexpress MYC. The expansion of cells containing deregulated MYC increases the probability of acquisition of a secondary mutation, which leads to tumor progression. After tumor progression, immune regulation selects against high levels of LMP2A in tumor cells, resulting in low levels of LMP2A in tumor biopsies. LMP2A is indicated by the multi spanning transmembrane protein. Constitutive MYC expression either by translocation or transgene construct is indicated by black/grey line in nucleus.
*Figure 2 and Figure 3 are adapted from ref 94.