EXPRESSION OF THE EPSTEIN-BARR-VIRUS (EBV)-ENCODED MEMBRANE-PROTEIN LMP1 IMPAIRS THE INVITRO GROWTH, CLONABILITY AND TUMORIGENICITY OF AN EBV-NEGATIVE BURKITT-LYMPHOMA LINE

In a previous study on several independently established Epstein-Barr virus (EBV)-converted sublines of the EBV-negative Burkitt lymphoma (BL) line BL41, we found that expression of the virally encoded membrane protein LMP1 was accompanied by reduced agarose clonability and tumorigenicity. In order to investigate whether LMP1 can induce these phenotypic changes by itself, we have now studied the growth in suspension culture, the clonability in agarose and the tumorigenicity in immunosuppressed and SCID mice of 4 LMP1-transfected sublines of BL41 that carry the gene under the control of the ZnSO4-inducible metallothionein promoter. Expression of LMP1 at levels comparable to those detected in EBV-transformed lymphoblastoid cell lines (LCL) correlated with impairment of growth in suspension and reduction of clonability and tumorigenicity. Only minor changes were observed in transfectants expressing low LMP1 levels. Up-regulation of LMP1 by ZnSO4 treatment of the low LMP1 clone MTLM5 was accompanied by a slowing down of proliferation, increased cell clumping and decreased clonability. The results suggest that expression of LMP1 at levels which are compatible with immortalization of normal B-cells antagonizes the ability of BL cells to grow in vitro and in vivo, and illustrate a possible mechanism by which down-regulation of this viral antigen may favor tumorigenicity in EBV-carrying BLs.