The Role of p53 in C-myc Induced Lymphomagenesis Mediated by the IgH 3′ Enhancers.

Translocation of the c-myc oncogene to the immunoglobulin heavy chain gene (IgH) locus is the most common chromosomal abnormality in Burkitt’s lymphoma. Our mouse model (IgH-3′E-myc) with the IgH 3′ enhancers integrated 5′ of the c-myc gene demonstrated that the IgH 3′ enhancers play an important role in c-myc deregulation and B cell lymphomagenesis. In this study, we examined the role of the tumor suppressor p53 in c-myc-induced B cell lymphomagenesis by developing IgH-3′E-myc mice with only a single p53 allele (p53^+/−-myc^E mice). We found that lymphoma development and death were significantly accelerated in these mice compared to the IgH-3′E-myc mice. p53^+/−-myc^E mice developed Burkitt-like B cell lymphomas at about 5 months of age, and the lymphomas had a clonal origin. In premalignant B cells, p53 expression was comparable to that in wildtype B cells; however, significantly decreased p53 levels were observed in malignant lymphoma cells. In addition, p53 expression was not up-regulated in response to etoposide in lymphoma cells. The remaining p53 allele was present, and no mutations were detected in the coding region. Increased expression of Mdm2 was observed in half of the lymphomas. Premalignant B cells from p53^+/−-myc^E mice showed higher induced and spontaneous apoptosis due to increased c-myc expression. However, malignant lymphoma cells had a greatly increased survival rate in culture and were more resistant to chemotherapeutic agents. The majority of the lymphomas showed increased expression of the anti-apoptotic protein Bcl-xL. We found that p53 could negatively regulate the bcl-xL promoter in lymphoma cells, and a region that was responsive to p53 in the bcl-xL promoter was identified. These data support the conclusion that decreased p53 levels and overexpression of Bcl-xL play an important role in c-myc-induced lymphomagenesis mediated by IgH 3′ enhancers.