Cellular interactions in the microenvironment of chronic lymphocytic leukaemia

慢性淋巴细胞白血病微环境中的细胞相互作用

• 批准号: 329053948
• 负责人: Dr. Charlotte Schmidt-Hieber
• 金额: --
• 依托单位: U653, Immunité et Cancer
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/329053948?language=en
• 关键词: Cellular; interactions; microenvironment; chronic; lymphocytic

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and currently not curable by conventional therapy. Interaction between CLL cells and bystander cells in lymph nodes and bone marrow is essential for establishment of the disease and leads to chemotherapy resistance. In order to disrupt the support that is sustaining CLL, further research is needed not only on the nature and effects of protective factors released by bystander cells, but also on the manipulation mechanisms used by CLL cells to receive them. One pivotal survival stimulus for the malignant cells is activation of their B cell antigen receptor (BCR) and clinical use of substances blocking BCR downstream signalling has led to impressive therapeutic responses, but not to cure from the disease. Molecular research showed persistent activation of downstream targets under efficient BCR blockade, and a recent study has identified the insulin-like growth factor 1 receptor (IGF1R) as an important candidate for alternative pathway activation. We could show that in fact, dual BCR and IGF1R blockade leads to a synergistic decrease in CLL cell viability in stromal cell co-culture. Since this effect was independent of IGF1R expression in the CLL samples examined, we hypothesise that part of the effect might be due to the impact of IGF1R blockade on co-cultured stromal cells. The aims of the proposed project are to identify the molecular effect of combined BCR and IGF1R blockade in CLL and stromal cells, the mechanisms used by CLL cells to manipulate bystander cells and the functional relevance of cross talk between bystander cells. We will use in vitro co-culture systems with CLL, stromal and monocytic cells and analyse cross talk and signal integration in the respective cell types through gene expression profiling and use of a novel bioinformatic analysis pipeline that has been established in the host laboratory. Complementary protein, phosphorylation and cytokine analysis will be performed for intracellular and soluble factors. To assess the significance of cross talk with CLL and stromal cells for immunological properties of the monocytic cells, we will examine cellular migration in organotypic culture and monocytic surface markers, cytokine secretion, phagocytic function and functional T cell interaction. These experiments may reveal targetable molecular mechanisms for novel therapeutic approaches that may ultimately yield deeper or even complete remissions in CLL patients.

慢性淋巴细胞白血病（CLL）是西方世界最常见的白血病，目前无法通过常规治疗治愈。CLL细胞与淋巴结和骨髓中的旁观者细胞之间的相互作用对于疾病的建立是必不可少的，并导致化疗耐药性。为了破坏维持CLL的支持，不仅需要进一步研究旁观者细胞释放的保护因子的性质和作用，还需要研究CLL细胞接收保护因子的操纵机制。恶性细胞的一个关键的存活刺激是其B细胞抗原受体（BCR）的活化，并且阻断BCR下游信号传导的物质的临床使用已经导致令人印象深刻的治疗反应，但不能治愈疾病。分子研究表明，在有效的BCR阻断下，下游靶点持续活化，最近的一项研究已将胰岛素样生长因子1受体（IGF1R）确定为替代途径活化的重要候选者。我们可以证明，事实上，双重BCR和IGF1R阻断导致基质细胞共培养中CLL细胞活力的协同降低。由于这种作用是独立的IGF1R的表达在CLL样本检查，我们假设，该效果的一部分可能是由于IGF1R阻断共培养的基质细胞的影响。拟议项目的目的是确定联合BCR和IGF1R阻断在CLL和基质细胞中的分子效应，CLL细胞操纵旁观者细胞的机制以及旁观者细胞之间串扰的功能相关性。我们将使用CLL，基质和单核细胞的体外共培养系统，并通过基因表达谱和使用已在宿主实验室建立的新型生物信息学分析管道来分析各自细胞类型中的串扰和信号整合。将对细胞内和可溶性因子进行互补蛋白、磷酸化和细胞因子分析。为了评估与CLL和基质细胞的单核细胞的免疫学特性的串扰的意义，我们将检查在器官型培养和单核细胞表面标志物，细胞因子分泌，吞噬功能和功能性T细胞相互作用的细胞迁移。这些实验可能揭示新的治疗方法的靶向分子机制，最终可能在CLL患者中产生更深甚至完全的缓解。