KSHV-encoded vIL-6 collaborates with deregulated c-Myc to drive plasmablastic neoplasms in mice

The mechanism by which Kaposi sarcoma (KS)-associated herpesvirus (KSHV), now recognized as human HV-8 (HHV-8), drives cancer is poorly understood. 1 In addition to KS, the virus causes life-threatening pathologies of the mature B-lymphocyte lineage, 2 including multi-centric Castleman’s disease (MCD), 3 diffuse large B-cell lymphoma evolving from MCD (MCD-DLBCL) 4 and primary effusion lymphoma (PEL). 5 These B-cell disorders are a significant public health concern because KSHV is frequently associated with HIV, which by itself increases the risk of developing B-lymphoma by ~2 orders of magnitude. In addition, the broad implementation of highly effective antiretroviral therapy has inadvertently caused a spike in lymphoma-related morbidity and mortality due to increased survival of HIV patients. Here, we took advantage of the laboratory mouse to enhance our understanding of KSHV-dependent pathophysiology in the B-lymphocyte lineage. Specifically, we evaluated the hypothesis that a KSHV-encoded cytokine, viral interleukin-6, hereafter called vIL-6, may be a driver of the transformation of B-lymphocytes to a malignant state. Our experimental strategy included the refinement of a recently developed C57BL/6 (B6) mouse model of constitutive, H2-K promoter-driven, transgenic (TG) vIL-6 expression 6 by making two critical changes. First, we backcrossed the vIL6 transgene from the genetic background of B6 onto BALB/c (C), an inbred strain of mice that is hyper-susceptible to malignant plasma cell tumors, such as inflammation-dependent peritoneal plasmacytoma. 7 Second, we intercrossed the newly generated C.vIL6 congenic mice with C.iMycΔEμ mice, a gene-insertion model of the chromosomal translocation T(12;15) that results in the deregulated expression of the cellular oncogene Myc in the B-cell lineage. We found that single-TG C.vIL6 mice are prone to a severe and sometimes fatal MCD-like disease, whereas double-TG C.vIL6iMyc mice invariably developed aggressive plasmablastic neoplasms that exhibited striking clinical and histopathological similarities to human PEL, plasmablastic lymphoma (PBL) and immunoglobulin (Ig)-producing, extramedullary plasmablastic plasma cell myeloma (PBM). The new findings will be briefly summarized below.