Inhibition of KSHV infected primary effusion lymphomas in NOD/SCID mice by γ-secretase inhibitor

Primary effusion lymphoma (PEL) is a common cancer in AIDS patients closely associated with Kaposi's sarcoma-associated herpesvirus (KSHV). Previously, we showed that KSHV latency associated nuclear antigen (LANA) stabilizes intracellular activated Notch I (ICN) involved in maintenance of the malignant phenotype of KSHV infected PEL cells in vitro. The gamma-secretase inhibitor (GSI) which specifically blocks the production of ICN slows down the proliferation of the KSHV infected PEL cell lines BCBLI, BC3 as well as JSCI in vitro. In this study, we extended these studies to explore the possibility that manipulation of the Notch signaling by GSI would prevent the growth of the PEL tumors in vivo. We observed that the onset of tumorigenesis of KSHV infected PELs was significantly delayed in GSI treated SOD mice harboring the PEL cell lines. We also found that GSI treatment resulted in necrosis as well as apoptosis in tumors generated by the xenotransplanted KSHV positive PEL cell lines. In contrast, GSI had no effect on mice harboring BJAB cells, a KSHV negative Burkitt's lymphoma cell line where ICN levels were negligible. Our study provides further evidence to suggest that targeted downregulation of abnormal Notch signaling has therapeutic potential for KSHV related primary effusion lymphomas.