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

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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.