Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of organ transplantation and is commonly associated with Epstein Barr virus (EBV) infection. EBV viral loads are typically monitored by qPCR in patients at risk of EBV+ PTLD, but EBV viremia does not always portend PTLD, and EBV+ PTLD can occur in the absence of increased viral levels. Thus, new biomarkers that herald the onset of EBV+ PTLD are needed and could facilitate the earlier intervention that is critical to improving patient outcomes. MicroRNA (miR) are a class of small non-coding RNA that are important in post-transcriptional regulation of cellular genes and may be useful as biomarkers since they can be found in a stable form in the blood and within exosomes. In the current study we asked whether EBV alters the host B cell miR network and whether unique changes in miR profiles are associated with EBV+ PTLD. qPCR arrays were used to measure expression levels of 639 previously identified miR in RNA isolated from normal human B cells (n=4), lymphoblastoid cell lines (LCL) generated in the laboratory with the B95.8 strain of EBV (n=4) and EBV+ B lymphoma cell lines from patients with PTLD (n=6). One-way ANOVA analysis (P<0.01) was used to identify the miR differentially modulated within the 3 groups. 133 miRNA were significantly modulated by EBV infection, the majority of those miRNA (31 increased, 79 decreased) were similarly modulated in both LCL and EBV+ PTLD-derived cell lines. However, sixteen miRNA (13 up, 3 down) were uniquely modulated in EBV+ PTLD-derived cell lines whereas decreased expression of nine miRNA was observed only in LCL. Principal component analysis (PCA) revealed that 59.5% of sample variance was attributed to miR differences in normal B cells compared to EBV-infected B cells, whereas 13.7% of the variance was due to miR differences between LCL and EBV+ PTLD cell lines. These data indicate that EBV+ B cell lymphomas from patients with PTLD have unique miR signatures that distinguish them from normal B cells and from LCL generated in vitro. miR that are increased in EBV+ B cell lymphomas are excellent candidates for biomarkers of EBV+ PTLD.

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