*Purpose: Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of organ transplantation characterized by abnormal proliferation of lymphoid cells in the setting of immunosuppression. Epstein-Barr virus (EBV) is responsible for abnormal lymphocyte proliferation in the majority of PTLDs. Latent membrane protein 1 (LMP1) is the chief oncogenic protein of EBV. LMP1 can activate several cellular signal transduction pathways.

*Methods: Our laboratory has shown that LMP1 isolated from EBV-associated B cell lymphoma lines of PTLD patients contains gain-of-function mutations at AA212 (G>S) and AA366 (S>T) that result in sustained ERK signaling, c-Fos activation, and AP-1 activity. In this study, we asked whether these mutations are also present in tumors from patients with PTLD. DNA was isolated from formalin-fixed paraffin-embedded tissue sections of EBV+ PTLD tumors (n=8). Nested PCR was used to amplify LMP1, and the PCR products generated were cloned and sequenced.

*Results: Seven of eight tumors demonstrated both gain-of-function mutations. Interestingly, six of eight tumors contained an extra repeat of 11 amino acids within the LMP1 signaling tail corresponding to a putative JAK3 binding motif. However, a five amino acid sequence, HDPLP, within the Box-1 JAK3 putative binding region of LMP1, which is commonly detected in healthy individuals and wild-type EBV was detected in only 25% of the PTLD tum

*Conclusions: These data indicate that gain of function mutations in LMP1 are present in primary PTLD tumors. In addition, LMP1 sequences from the EBV+ B cell lymphomas lack the five amino acid, HDPLP motif, found in the Box-1 JAK3. These findings suggest that characteristic genomic variations in EBV may be associated with PTLD.

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