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

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.

Acute myeloid leukaemia (AML) is an age-related disease that is highly dependent on the bone marrow (BM) environment. My group has recently shown that AML acquires functional mitochondria from the bone marrow environment through tunneling nanotubules, and that this promotes AML survival and proliferation. Moreover, we have found this increase in functional mitochondria to significantly increase oxidative phosphorylation in AML cells when compared with non-malignant haematopoietic progenitor cells. To further understand how AML maintain a functional pool of mitochondria this project will determine how AML regulates the disposal of mitochondria and also determine the impact of this disposal system on AML survival and proliferation. First, we plan to confirm preliminary findings which show that mitochondria are removed from AML in large extracellular vesicles. Then we will establish what impact AML derived mitochondria have on bone marrow associated macrophages. Finally, we will determine the impact if BM macrophages on AML survival and proliferation. Together, the data generated in this proposal could yield a substantial advancement in the understanding of AML pathobiology. which in future may allow the development of new treatment targets.

With over 3,000 new cases of acute myeloid leukaemia (AML) in the UK per year and over 350,000 new cases globally, combined with the statistic that at least 75% of people diagnosed die within the first 12 months, AML represents a leading cause of death worldwide and therefore comes with a financial and emotional cost to our society. Moreover, the incidence of AML increases with age and, as our aging population grows, the burden of AML upon our patients and society grows.

Despite 50 years of drug developments and trials of therapies targeting the leukaemic cancer cell, the outcomes have largely failed to significantly improve for the majority of patients. Novel and more directed approaches, beyond cytotoxic chemotherapy, with improved efficacy and reduced side effect profiles are envisaged to be necessary to improve outcomes in this presently highly lethal disease. Because almost all patients die as a result of a failure to eradicate AML from the bone marrow, understanding how leukaemic cells within the bone marrow microenvironment interact with AML cells and support AML disease survival is critically important if we want to realise our goal of improving patient outcomes. Furthermore, these new therapies must be suitable for our older, frailer patients who represent the majority of patients who are diagnosed with and die of AML.

The Norwich haematology team has a track record in translating scientific findings into the clinic by teaming up with academic and industrial partners (Pharmacyclics, Abbivie and Aptose Bioscience). For example, NCT03267186, NCT0235103, NCT02635074 and HOVON 135 AML / SAKK are Phase II clinical trials based on our previous findings. Moreover, working with Aptose Bioscience we have developed new compounds targeting molecules that our group has identified as therapeutically relevant for AML. Together, this places our group in a unique position as we can apply the knowledge gained during this study and team up with existing partners to develop novel treatment strategies to benefit patients with AML. Thus our proposal may deliver social impact by providing new targets for our industrial partners to develop new treatment options leading to enhanced quality of life and health for patients who currently have limited treatment options and a very short life expectancy. It is therefore envisaged that patients and patients groups such as Leukaemia CARE and the AML. It will also provide knowledge to patient groups and charities which will help raise awareness of the disease. We hope that our findings may also be of relevance to other cancers in which the tumour microenvironment plays a crucial role, which will significantly increase the social and economic impact.

Most people diagnosed with 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 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.