Dissecting Lymphoma Niche Interactions

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Lymphomas, the most prevalent cancer of immune cells require contact to various other cell-types in their direct vicinity, collectively referred to as niche. When taken out of an organism and cultured in absence of supporting niche cells, lymphoma cells typically die quickly. Therefore, niche cells are essential for the survival and proliferation of lymphoma cells in vivo and in vitro, through secreted soluble factors and cell-cell contacts. In recent years, it became clear that lymphomas do not simply settle in preformed niches, but in contrast actively induce a niche microenviroment that then sends critical survival signals back to the lymphoma cells. Chronic lymphocytic leukemia (CLL) is an essentially incurable disease of cancerous B cells that expand and survive in niches at different bodily locations. Niche cells also provide protection for CLL cells against cytotoxic therapies and therefore contribute essentially to therapy resistance. CLL cells induce activation of the NF-kappaB family of transcription factors in stromal cells, which control the production of essential proteins for the survival of CLL cells. This occurs through the induction of the PKCbeta-II kinase in stromal cells, an important niche subpopulation, through signals initiated via direct CLL-stroma interactions. The relevance of this signaling pathway was unambiguously demonstrated through adoptive transfer of mouse Tcl1tg CLL cells into wild-type mice and mice lacking PKCbeta: malignant CLL cells only expanded in wild-type, but not in PKCbeta-deficient mice. In our proposal we will test various relevant proteins and cellular pathways, which are induced by CLL cells in the stroma for their role in providing survival signals back to the CLL cells. The effects will be monitored in absence and presence of cytotoxic chemotherapies. Furthermore, we will investigate the CLL-induced signals in stromal niche cells in detail and test the hypothesis that CLL cells carrying mutations that provide therapy-resistance induce different signals. Finally, we will employ a preclinical mouse model to characterize the CLL-maintaining niche subpopulations in vivo and to dissect their individual and potentially redundant roles in CLL support.