Molecular and Cellular Basis of Clonal Dominance in Myeloid Malignancy

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Humans produce around 100 billion new blood cells daily to survive. Occasionally mistakes occur in this complex process, which may lead to blood cancer, including acute myeloid leukaemia (AML). AML is the most common aggressive blood cancer in adults with 3000 new cases per year in the UK, and unfortunately the majority still die of their disease within 6 months of diagnosis. A better understanding of the biology of the disease is needed to improve the outcome for these patients.AML arises as a result of multiple mistakes, or mutations, in genes that control blood production. These mutations usually occur in a step-wise manner over time in a small pool of blood stem/progenitor cells (the cells that give rise to all the blood cells we need). Recently it was discovered that some of these mutations are commonly found in the blood cells of healthy older people who do not have yet have blood cancer. These mutations appear to make the cells grow more than is normal, so that over time they dominate the bone marrow (where blood is produced), and increase the risk of developing blood cancers in the future.The most common of these mutations occur in genes which control "epigenetic" marks on the DNA. Epigenetic marks do not affect the DNA sequence, but can contribute to disease as they control how genes are switched on and off. In this project, we are studying how mutations in these epigenetic regulators turn normal blood stem cells into abnormal "preleukaemic" cells that can go on to cause AML. We aim to find out which blood cells get the mutations and which pathways in these cells make them grow abnormally.To do this, we will be studying blood cells from healthy human volunteers who have donated bone marrow samples obtained during hip or knee operations, from patients with AML and in mice with one of the mutations. Our experiments will help us to work out how the mutations change the way cells behave and what genes are switched on and off abnormally. We will then use this knowledge to try to find a pathway that can be blocked to stop the cells growing.This research is important for two reasons. Firstly, it will give us a better understanding of how AML and other blood cancers develop. Secondly, we hope that it will identify a way to kill the preleukaemic cells to prevent leukaemia before it fully develops, and to improve treatment for patients with AML.