Dissecting Lymphoma Niche Interactions

淋巴瘤是最常见的免疫细胞癌症，需要与直接邻近的各种其他细胞类型接触，这些细胞类型统称为生态位。当从生物体中取出并在缺乏支持龛细胞的情况下进行培养时，淋巴瘤细胞通常会很快死亡。因此，通过分泌可溶性因子和细胞间接触，生态位细胞对体内和体外淋巴瘤细胞的存活和增殖至关重要。近年来，人们清楚地认识到，淋巴瘤并不简单地定居在预先形成的生态位中，相反，它积极地诱导一个生态位微环境，然后将关键的生存信号传回淋巴瘤细胞。慢性淋巴细胞白血病（CLL）是一种本质上无法治愈的疾病，癌细胞B细胞在身体不同部位的壁龛中扩张和生存。小生境细胞也为CLL细胞提供保护，使其免受细胞毒性疗法的侵害，因此在本质上有助于治疗耐药性。CLL细胞诱导基质细胞中NF-kappaB家族转录因子的激活，这些转录因子控制着CLL细胞存活所需蛋白质的产生。这是通过在基质细胞（一个重要的生态位亚群）中通过直接cll -基质相互作用启动的信号诱导pkc - β - ii激酶发生的。通过将小鼠Tcl1tg CLL细胞过代转移到野生型小鼠和缺乏PKCbeta的小鼠中，明确证明了这一信号通路的相关性：恶性CLL细胞仅在野生型小鼠中扩增，而在PKCbeta缺陷小鼠中没有扩增。在我们的提案中，我们将测试由基质中CLL细胞诱导的各种相关蛋白和细胞通路，以了解它们在向CLL细胞提供生存信号方面的作用。将在没有和有细胞毒性化疗的情况下监测其效果。此外，我们将详细研究基质生态位细胞中CLL诱导的信号，并验证携带提供治疗抗性突变的CLL细胞诱导不同信号的假设。最后，我们将采用临床前小鼠模型来表征体内维持CLL的生态位亚群，并剖析它们在CLL支持中的个体和潜在冗余作用。

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.