Investigation of the processes determining mitochondrial fate in normal and malignant haematopoiesis

大多数被诊断为急性髓系白血病(AML)的人死于这种疾病，因为目前可用的针对AML细胞的化疗无法从骨髓中根除白血病。在一定程度上，这是因为骨髓环境促进了白血病的生长，并提供了免受药物治疗的保护。预计未来针对环境和肿瘤(土壤和种子)的治疗策略将改善患者的预后。该项目旨在了解骨髓对癌症的特定保护功能，以期在未来确定新的治疗策略。我们最近发现，AML细胞从它们增殖的环境中获得能量需求。他们通过从骨髓的其他细胞获取线粒体(细胞的动力装置)来做到这一点。这支持了ATP(能量)产量的增加，这推动了白血病细胞的生存和快速增殖。在这个项目中，我们假设AML通过将旧线粒体以称为囊泡的小块形式从细胞中排泄出来来处置旧线粒体。然后，这些小泡被称为巨噬细胞的细胞吃掉，巨噬细胞是骨髓的监测系统。免疫系统是我们抵抗癌症的天然防御系统之一，众所周知，它是根除癌症的过程的一部分。在这个项目中，我们建议了解白血病中的小泡是如何导致巨噬细胞衰竭的，因此，如果我们能够阻止AML排泄小泡或防止巨噬细胞吞噬它们，这可能会确定新的治疗靶点，以帮助治疗这种疾病。

Most people diagnosed with Acute Myeloid Leukaemia (AML) die of the disease because currently available chemotherapy targeting AML cells cannot eradicate the leukaemia from the bone marrow. In part, this is because the bone marrow environment promotes leukaemia growth and also provides protection from the drug treatment. It is envisaged that future treatment strategies targeting the environment and the tumour (the soil and the seed) will lead to improved outcomes for patients. This project looks to understand cancer specific protective functions of the bone marrow with a view to identify novel therapeutic strategies in the future. We have recently discovered that AML cells acquire their energy needs from the environment in which they proliferate. They do this by acquiring mitochondria (power plant of the cell) from other cells of the bone marrow. This supports the increased production of ATP (energy) which drives the survival and rapid proliferation of leukaemic cells. In this project we hypothesise that AML disposes of old mitochondria by excreting them from the cell in small parcels called vesicles. These vesicles are then eaten by cells known as macrophages which are the surveillance system of the bone marrow. The immune system is one of our natural defences against cancer and is known to form part of the process that can eradicate the disease. We propose in this project to understand how the vesicles from the leukaemia causes failure of the macrophages, and therefore if we could stop AML excreting the vesicles or prevent macrophages from eating them, this could identify new therapeutic targets to help treat this disease.