Characterisation of the PKC-beta-NF-kB signalling pathways activated in the bone marrow niche of chronic lymphocytic leukaemia

尽管肿瘤细胞中的许多基因组畸变影响着程序性细胞死亡，但它们的存活并不是细胞自主的，而是高度依赖于微环境提供的促存活信号。在这方面，来自慢性淋巴细胞白血病（CLL）患者的恶性B细胞通过与骨髓源性基质细胞（BMSCs）接触而免受自发和药物诱导的凋亡。我们最近已经证明恶性B细胞通过重新编程骨髓间充质干细胞来创造自己的生态位，从而在基质细胞中表达促炎基因。CLL诱导的蛋白激酶C-β (PKC-β)的表达和NF-κB的激活是基质细胞促进恶性B细胞存活的先决条件。本研究计划旨在了解PKC- β诱导的微环境重塑如何影响白血病细胞的存活。此外，我们想要解决骨髓间充质细胞中的信号传导如何在CLL的生态位依赖性生存中实现，以及Notch的激活是否影响骨髓间充质细胞中的PKC-β - NF-κ b生存信号通路。通过过继性转移实验和NF-κB报告小鼠，我们将在体内确定CLL骨髓生态位的空间条件。我们期望我们的研究结果将有助于通过干扰关键的肿瘤-宿主相互作用来确定癌症治疗的新药物靶点。

In spite of numerous genomic aberrations affecting the programmed cell death in tumour cells, their survival is not cell autonomous, but highly dependent on pro- survival signals provided by the microenvironment. In this respect, malignant B cells from patients with chronic lymphocytic leukaemia (CLL) are protected from spontaneous and drug induced apoptosis by contact with bone marrow derived stromal cells (BMSCs). We have recently demonstrated that malignant B cells create their own niche by reprogramming BMSCs, imposing the expression of proinflammatory genes in stromal cells. CLL induced expression of protein kinase C-β (PKC-β) and activation of NF-κB are prerequisites for stromal cells to promote the survival of malignant B cells. This research proposal aims at understanding how PKC- β induced remodelling of the microenvironment affects survival of leukemic cells. Furthermore, we want to address how signalling in BMSCs is implemented in niche dependent survival of CLL and whether activation of Notch impinges on the PKC-β - NF-κB survival signalling pathway in BMSCs. By using adoptive transfer experiments and a NF-κB reporter mouse we will define the spatial conditions of the bone marrow niche in CLL in vivo. We expect that results from our studies will help defining new drugtargets for cancer therapies by interference with crucial tumour-host interactions.