Multiple myeloma (MM) is a hematologic malignancy which affects 14,400 new individuals in the United States annually and is incurable whether conventional approaches or high dose therapies are used. Novel treatment approaches are therefore needed which target mechanisms whereby MM cells grow and survive. This project to date has sponsored the PI's studies in which he has demonstrated both in vitro and using in vivo murine models that interleukin-6 (IL-6) is an autocrine growth factor, as well as an anti-apoptotic factor, for human MM cells. The PI has also characterized the signaling cascades mediating these events. Although there is strong evidence for the role of IL-6 in growth and survival of human MM cells, some MM cells grow in an IL-6 independent fashion, and it remains possible that other factors may contribute to MM pathogenesis. Of great interest in this regard is the recent identification by others and the PIs laboratory of infection of MM bone marrow stromal cells (BMSCs) with Kaposi's sarcoma associated herpesvirus (KSHV). KSHV genome encodes for vial IL-6 (vIL-6), a homologue of human IL-6; however, the role of KSHV in the pathogenesis of MM and of vIL-6 in the growth and survival MM is undefined. The PI intends to extend his studies to characterize the role of vIL-6 compared with human IL-6 in the in vitro and in vivo growth and survival of human MM cells. The PI will identify KSHV infection in human MM and the lineage of the infected cell. The PI will characterize the role and regulation of vIL-6 production in the autocrine nd paracrine growth of MM using his well established in vitro models, and delineate the signaling cascades whereby MM cell proliferation triggered via vIL-6 is mediated. Given the PI's prior experience that IL-6 is an anti-apoptotic factor in MM, he will determine whether vIL-6 is also a survival factor of human MM and delineate the signaling cascades medication the anti-apoptotic effect of vIL-6 compared with human IL-6. Finally, the PI plans to extend these in vitro observations to the in vivo setting using his SCID-hu mouse model, which will allow him to both directly examine the significance of KSHV infection within the BM in the pathogenesis of MM and define the role of vIL-6 in the autocrine and paracrine growth and survival of human MM cells. The PI's proposed experiments will define the significance of KSHV infection and MM and may provide the basis for novel treatment approaches which target KSHV or vIL-6 in MM.
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