Epigenomic Mechanisms of Action of Novel Mutant Isocitrate Dehydrogenase Inhibitors in Acute Myeloid Leukaemia

Acute myeloid leukaemia (AML) is a most common aggressive leukaemia in adults and is incurable in most patients. In AML, gene mutations cause immature cells in bone marrow to stop making mature cells (differentiation block and bone marrow failure) and to increase is numbers in patient bone marrow (expansion). Patients develop symptoms of anaemia, bleeding and infections, which lead to death is untreated. Most effective treatments for AML use chemotherapy drugs which kill leukaemic cells. These are highly toxic as they also harm other cells in the body. The majority of patients with AML are elderly and unable to tolerate these types of treatment. We therefore need to have more effective, less toxic treatments to restore blood and bone marrow function (disease remission) to both improve rates of cure, prolong patient survival, improve quality of life. 20% of AML patients have a mutation in genes coding for the enzymes isocitrate dehydrogenase 1 or 2 (IDH1/2). The mutant enzyme (mIDH) produces an abnormal chemical (or metabolite), dextro-2-hydroxyglutarate (d2HG). This metabolite is known to cause cancer (including AML and brain tumours), most probably by stopping cells from maturing properly. New drugs which inhibit mIDH (mIDHi), is effective for ~40% of Isocitrate Dehydrogenase mutant (IDHm) AML patients. It works by reducing the number of immature AML cells by causing them to become useful mature blood cells. This benefits patients by reducing the need for blood transfusions and infection risk. Unfortunately, most patients who initially respond to mIDHi will develop resistance and relapse. We do not understand why this happens, or why some patients never respond to mIDHi. We also do not fully understand how mIDHi work, but it is likely to involve changes to the control mechanisms of genes To address these fundamental questions, I want to understand what goes wrong in the control mechanism of genes which are usually expressed when blood cells mature, and how this causes AML. The aims of my proposal is to 1) Study how blood cells differentiate and mature in normal bone marrow and how this process of differentiation and maturation goes wrong in AML (i.e. differentiation block) 2) Investigate how drugs like mIDHi are able to re-programme AML cells to make them differentiate into functional mature cells 3) In patients where mIDHi are not effective, or when a patient's disease becomes resistant to mIDHi, find out why AML cells remain, or become blocked. If I can discover how we can target these blocked pathways, for example, by using novel drugs or by combining the effects of mIDHi with other drugs, then this could be useful for treating patients. The methods I will use to study the behaviour of AML cells include using genetic sequencing techniques to look at how genes are expressed in cells, and also what the mechanisms are which control gene expression (epigenomics). This could provide a better characterisation and understanding of AML cells and be used to determine if AML patients are more or less likely to respond to a particular treatment. This can help clinicians to decide which treatments are best for an individual patient, and help develop combinations of treatments which are more likely to work for an individual.