Targeting IKKepsilon-mediated nucleotide synthesis in KSHV-associated lymphoma

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Abstract Title: Targeting IKKepsilon-mediated nucleotide synthesis in KSHV-associated lymphoma Human gamma herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are causative agents of diverse malignancies in immune- compromised individual, including AIDS patients and organ transplant recipients. In addition to KS, KSHV is invariably associated with two types of lymphoma, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). No vaccine or effective treatment is available for KSHV-associated malignancies, though antiviral therapy targeting viral thymidine kinase is an option with limited efficacy. We have an outstanding interest in virus-host interaction involving innate immune defense system. Recently, we discovered that KSHV exploits the IKKepsilon kinase to reprogram metabolism in KSHV latently-infected PEL cells. Specifically, KSHV activates IKKepsilon to fuel de novo nucleotide synthesis via activating key metabolic enzymes known as glutamine amidotransferases. In doing so, IKKepsilon promotes the proliferation of KSHV-infected PEL cells and depletion of IKKepsilon arrests these cells at G0/G1 phase. This study will delineate the molecular interaction that KSHV activates IKKepsilon in metabolic reprogramming to support immortal proliferation of PEL cells. We have developed novel small-molecule inhibitors of IKKepsilon and glutamine amidotransferases. We will explore these drug-like molecules to target IKKepsilon and glutamine amidotransferase to impede PEL cell proliferation. Our work will not only elucidate fundamental mechanism governing PEL cell metabolism and proliferation, but also provide proof-of-concept that targets host factors to treat KSHV-associated malignancies.