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Epstein-Barr virus latent membrane protein-1 oncogene deletions:
correlations with malignancy in Epstein-Barr virus--associated
lymphoproliferative disorders and malignant lymphomas
DW Kingma, WB Weiss, ES Jaffe, S Kumar, K Frekko and M Raffeld
Division of Cancer Biology, Diagnosis and Centers, National Cancer
Institute, National Institutes of Health, Bethesda, MD 20892-1500, USA.
LMP-1, an Epstein-Barr viral (EBV) latency protein, is considered a viral
oncogene because of its ability to transform rodent fibroblasts in vivo and
render them tumorigenic in nude mice. In human B cells, EBV LMP-1 induces
DNA synthesis and abrogates apoptosis. LMP-1 is expressed in
EBV-transformed lymphoblastoid cell lines, nasopharyngeal carcinoma (NPC),
a subset of Hodgkin's disease (HD), and in EBV-associated
lymphoproliferative disorders (EBV-LPDs). Recently, focused deletions near
the 3' end of the LMP-1 gene (del-LMP-1, amino acids 346-355), in a region
functionally related to the half-life to the LMP-1 protein, have been
reported frequently in human immunodeficiency virus (HIV)- associated HD
(100%) and EBV+ Malaysian and Danish peripheral T-cell lymphomas (100%, 61%
respectively), but less frequently in cases of HD not associated with HIV
(28%, 33%) and infectious mononucleosis (33%). To further investigate the
potential relationship of del-LMP-1 to EBV- LPDs associated with
immunosuppression or immunodeficiency, we studied 39 EBV-associated
lymphoproliferations (10 benign, 29 malignant) from four distinct clinical
settings: posttransplant (4 malignant, 1 reactive); HIV+ (18 malignant, 2
reactive); nonimmunodeficiency malignant lymphoma (ML) (7 cases); and
sporadic EBV infection with lymphoid hyperplasia (7 cases). The presence of
EBV within lymphoid cells was confirmed by EBV EBER1 RNA in situ
hybridization or by polymerase chain reaction (PCR) analysis. EBV strain
type and LMP-1 deletion status were determined by PCR. EBV strain types
segregated into two distinct distributions: HIV+ (9 A; 11 B) and non-HIV
(19 A, 0 B), consistent with previous reports. Overall, del-LMP-1 were
found in 1 of 5 (20%) Burkitt lymphomas (BL); 17 of 24 (71%) aggressive
non- Hodgkin's lymphoma (agg-NHL), and 2 of 10 (20%) reactive lymphoid
proliferations. Of the agg-NHLs, del-LMP-1 were present in 4 of 4 PT-ML
(100%); 10 of 15 HIV+ ML (67%); and 3 of 5 nonimmunodeficiency malignant
lymphoma (ML, 60%). A total of 2 of 7 (28%) sporadic EBV- associated
lymphoid hyperplasias contained a del-LMP-1. All del-LMP-1 were identical
by DNA sequence analysis. No correlation was identified between the
presence of del-LMP-1 and the EBV strain type observed. The high incidence
of del-LMP-1 observed in agg-NHLs (71%), in contrast to the relatively low
incidence observed in reactive lymphoid proliferations (28%), suggests that
the deleted form may be preferentially selected in lymphomatous processes.
All posttransplant agg-NHLs contained a del-LMP-1, and a similar frequency
of del-LMP-1 was observed in both HIV-associated ML (66%) and
nonimmunodeficiency ML (60%), suggesting that impairment of immune function
alone is not a requirement for the expansion of malignant cells infected by
EBV stains containing the deleted LMP-1 gene.
Volume 88,
Issue 1,
pp. 242-251,
07/01/1996
Copyright © 1996 by The American Society of Hematology
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