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 downregulation of abnormal Notch signaling has therapeutic potential for KSHV related primary effusion lymphomas.

ADAM10 Overexpression Shifts Lympho- and Myelopoiesis by Dysregulating Site 2/Site 3 Cleavage Products of Notch

“…The differential effects of S2 and S3 blockade on WT Notch signaling have significant implications for the treatment of Notchrelated diseases. Many reports have proposed the use of GSIs for the treatment of T-ALL and B cell lymphoma (14,44); however, our findings indicate that GSI treatment could cause MDSC expansion that would ultimately induce immunosuppression and enhance tumor growth. Thus, studies of GSI treatment in mice and clinical trials should include careful monitoring of myeloid cell development.…”

KSHV viral cyclin interferes with T-cell development and induces lymphoma through Cdk6 and Notch activation in vivo

“…GSI treatment of the KSHV-infected PEL cell lines leads to G1 cell cycle arrest in vitro 16 and induces cell death in PEL xenografts in mice. 19 These data suggest that inhibition of activated Notch signaling could have therapeutic potential for both KS tumors and KSHV-induced PELs.…”

“…Our study thus reveals new insights in KSHV pathogenesis by linking expression of a viral oncogene to Notch pathway activation, and further supports the earlier reports showing that inhibition of Notch might serve as a good strategy in treating KSHV-induced malignancies. 13,16,18,19 It is clear that this mouse model, in which v-cyclin is expressed in isolation of the other viral factors, only covers a small subset of all v-cyclin functions. Yet, this study reveals that v-cyclin expression in vivo not only recapitulates several of its properties identified in cell culture models, but also provides novel insights into KS/PEL pathogenesis.…”

Distinct Roles of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interferon Regulatory Factors in Inflammatory Response and Cancer

“…Activated Notch CSL/CBF1 signaling was shown to promote the survival of KSHV-infected cells (140,141,142). Notch signaling is an evolutionarily conserved signal transduction pathway which regulates multiple developmental processes.…”