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

Abstract

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 Notch1 (ICN) involved in maintenance of the malignant phenotype of KSHV

infected PEL cells in vitro. The γ-secretase inhibitor (GSI) which specifically blocks the

production of ICN slows down the proliferation of the KSHV infected PEL cell lines

BCBL1, BC3 as well as JSC1 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 SCID 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 down-regulation of abnormal Notch signaling has therapeutic potential for

KSHV related primary effusion lymphomas.

View correction statement:

Correction