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. 2009 Oct 20;106(42):17945-50.
doi: 10.1073/pnas.0907994106. Epub 2009 Oct 7.

Epstein-Barr virus LMP2A bypasses p53 inactivation in a MYC model of lymphomagenesis

Kathryn T Bieging  1 , Alexandra C Amick, Richard Longnecker
Affiliations

Epstein-Barr virus LMP2A bypasses p53 inactivation in a MYC model of lymphomagenesis

Kathryn T Bieging et al. Proc Natl Acad Sci U S A. .

Abstract

Although Epstein-Barr virus (EBV) is linked to Burkitt's lymphoma (BL), the role of the virus in lymphomagenesis is unclear. LMP2A, encoded by EBV, can be detected in BL biopsies and has prosurvival functions. We generated mice expressing MYC and LMP2A in B cells. LMP2A/lambda-MYC mice show greatly accelerated tumor onset. Similar to previous work, we found p53 mutations in lambda-MYC tumors; however, we detected no mutations in the rapidly arising LMP2A/lambda-MYC tumors. We further demonstrate that the p53 pathway is functionally intact in LMP2A/lambda-MYC tumors, which have increased levels of PUMA and sensitivity to p53 activation by Nutlin. This work shows that LMP2A can permit tumorigenesis in the presence of an intact p53 pathway, identifying an important contribution of EBV to BL.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
LMP2A/λ-MYC transgenic mice show accelerated tumor onset, and tumors lack p53 and p19 ARF stabilization. (A) Kaplan–Meier curve shows percentage survival of each transgenic line. Mice were killed when cervical lymph node tumors were observed, at which point the animals could generally survive for a maximum of 7 days. (B) p53 and p19 ARF are stabilized in tumors from λ-MYC mice, but not in LMP2A/λ-MYC tumors. Lysates were made from cervical lymph node tumor cells (CT) and splenocytes (SP) from tumor-bearing λ-MYC and LMP2A/λ-MYC mice. Lysates were probed for p53 and p19 ARF in addition to c-Myc and LMP2A to confirm transgene expression.
Fig. 2.
Fig. 2.
The p53 pathway is intact in LMP2A/λ-MYC tumor cells. (A and B) Freshly isolated cervical lymph node (CT) or spleen (SP) tumor cells from λ-MYC and LMP2A/λ-MYC mice were plated in increasing concentrations of Nutlin 3 at 2.5 million cells per mL. Viable cell number was determined using trypan blue exclusion. (C) Tumor cells from the cervical lymph node (CT) and spleen (SP) of λ-MYC mice were grown in culture for several weeks, and then plated in increasing concentrations of Nutlin 3 at 1.5 million cells per mL. Viable cell number was determined using trypan blue exclusion. (D) Nutlin 3 treatment induces p53 in LMP2A/λ-MYC tumor cells. Splenocytes from LMP2A/λ-MYC tumor-bearing mice were isolated and immediately plated in increasing concentrations of Nutlin 3. Cells were harvested 8 h after treatment, lysed, and probed for p53. (E) PUMA levels are increased in LMP2A/λ-MYC tumor cells. Freshly isolated λ-MYC and LMP2A/λ-MYC cervical tumor cells (CT) and splenic tumor cells (SP) were lysed and probed for PUMA.
Fig. 3.
Fig. 3.
Model for the role of LMP2A in development of Burkitt's lymphoma in mice and humans. (A) In the λ-MYC mouse model, MYC is expressed in B cells throughout B cell development. Deregulated MYC expression results in induction of apoptosis through p53 pathway activation. Burkitt's lymphoma-like tumors are observed in these mice upon mutation of one or more components of the p53 pathway. (B) Both LMP2A and MYC are expressed throughout B cell development in the LMP2A/λ-MYC transgenic mouse. The MYC transgene activates the p53 pathway, but LMP2A is able to counteract this activation, likely at some step that is downstream of PUMA, perhaps through up-regulation of Bcl-XL. LMP2A causes an initial expansion of cells, observed as splenomegaly in pretumor animals (spleen masses of 0.55 ± 0.17 g for LMP2A/λ-MYC and 0.17 ± 0.07 g for λ-MYC). In the absence of immune selection, LMP2A accelerates tumor onset in this model, allowing tumorigenesis in the presence of an intact p53 pathway. (C) In human BL, translocation of MYC to an Ig locus occurs in a germinal center reaction. MYC induces p53 pathway activation, resulting in apoptosis. Cells that have inactivated the p53 pathway grow into lymphoma. (D) In EBV-positive human BL, LMP2A is present during the germinal center reaction and MYC translocation. LMP2A likely enhances survival of cells with deregulated MYC early in lymphomagenesis, causing expansion of cells and increasing the probability of secondary mutation, which leads to tumor progression. After tumor progression immune regulation selects against high levels of LMP2A in tumor cells. LMP2A is indicated by the multi spanning transmembrane protein. Constitutive MYC expression either by translocation or transgene construct is indicated by black/gray line in nucleus.
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