Epstein-Barr virus latent membrane protein-1 oncogene deletion in post-transplantation lymphoproliferative disorders

Abstract

Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is a multifunctional oncoprotein. A 30-bp deletion of the 3' end of the LMP1 gene (del-LMP1) has been identified in some EBV isolates. This deleted LMP1 gene encodes a protein, altered on the carboxy terminus, which is thought to have greater oncogenic potential than the wild type. Recently, it was suggested that del-LMP1 plays a role in the development of malignant lymphomas occurring in immunocompromised patients. To further elucidate the role of del-LMP1 in post-transplantation lymphoproliferative disorders (PT-LPDs) we analyzed 58 PT-LPD lesions from 36 heart and kidney organ transplant recipients. Overall, del-LMP1 was detected in 44% of the cases. Four plasmacytic hyperplasias (36%), eight polymorphic B-cell hyperplasias/polymorphic B-cell lymphomas (38%), and five malignant lymphomas/multiple myelomas (71%) exhibited del-LMP1. Two of the three patients displaying disease progression showed wild-type LMP1 gene (w-LMP1) and one showed del-LMP1. LMP1 status remained the same in all three patients during disease progression. In patients undergoing biopsy of multiple separate PT-LPD lesions representing different clonal lymphoid proliferations, LMP1 status was the same in all of the lesions in each patient. Furthermore, although the polyclonal lesions harbor multiple EBV infectious events, they either showed w- or del-LMP1 but not both. Analysis of the tissues without an apparent PT-LPD (peripheral blood, bone marrow, or colon) revealed EBV and LMP1 type identical to that found in the lesions. In conclusion, the presence or absence of del-LMP1 in PT-LPDs does not correlate with the histopathological category or the malignant nature of the lymphoid proliferation. LMP1 status does not change during disease progression and is the same within multiple lesions occurring in the same patient regardless of their clonal relationship. These findings suggest that 1) EBV infection in patients with PT-LPDs occurs with a w- or del-LMP1-type EBV isolate and does not change once a patient acquires the virus and 2) the infection is an early event in the development of PT-LPDs and transformation is induced regardless of the type of LMP1.