Genomic Status of the Epstein Barr Virus and Virus-Associated PI3K/Akt/mTOR Pathway Dysregulation in Post-Transplant Lymphoproliferative Disorder

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Abstract

Epstein Barr Virus (EBV) is nearly ubiquitous across the human population, yet EBV infection is typically asymptomatic. Nevertheless, immunosuppressed transplant recipients are susceptible to EBV+ B cell lymphomas and post-transplant lymphoproliferative disorder (PTLD), which significantly contributes to mortality among these patients. Dysregulation of the host cellular PI3K/Akt/mTOR signal transduction pathway, induced by EBV latent cycle gene expression, may play a critical role in the pathogenesis of EBV+ PTLD and lymphoma proliferation. However, the specific changes to the PI3K/Akt/mTOR pathway and other host cellular network alterations in EBV+ PTLD are not well understood. Here we investigate genetic and epigenetic factors that may contribute to dysregulation of the PI3K/Akt/mTOR pathway in EBV+ PTLD. MicroRNA (miRNA) expression arrays were used to define the differences in the miRNA networks of tumor biopsies from patients diagnosed with EBV+ or EBV- PTLD as well as EBV+ lymphoblastoid cell lines. We identified 20 miRNA that were significantly upregulated in EBV+ PTLD that are predicted to target the tumor suppressor PTEN within the PI3K/Akt/mTOR pathway with a high precision threshold (miTG score > 0.6) by the DIANA-microT prediction algorithm. Molecular array analysis of PI3K pathway genes identified mutations within PTEN, PI3K, and STK11 in five EBV+ PTLD B cell lines and three primary PTLD lymphomas. Five distinct mutations were identified within the PTLD-derived cell lines and 25 distinct mutations were identified in EBV+ primary PTLD tumors. Four pathway mutations were shared between a cell line and one or more primary EBV+ tumor(s). In addition to host pathway dysregulation through EBV-induced changes, we also investigated the genomic status of EBV. Using cytogenetic approaches, the EBV genome was found to be in an integrated state in 3 of 3 PTLD cell lines analyzed. Viral integration sites were mapped to host chromosome arms and preferential integration sites were found in 4q, 5q, 6q, 13p, 13q and 16q. These results indicate that unique miRNA profiles and mutational alterations in the PI3K/Akt/mTOR pathway as well as integration of EBV into the host genome may contribution to B lymphocyte tumorigenesis.

Molecular and Cellular Immunobiology NIH Training Grant institutional postdoctoral fellowship (5 T32 AI07290). Stanford Neuroscience Microscopy Service, supported by NIH NS069375.

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