Genetics is complex! At a very basic level we understand that when genes are altered or mutated the end result is a disease. This can take the form of hereditary diseases such as cystic fibrosis, sickle cell anaemia or Huntington’s disease for example. However, gene mutations can also be spontaneous and sometimes result in cancer. It is now well established that many of these spontaneous mutations change the “epigenome”, information surrounding the DNA that is responsible for determining the function that a cell will play in the body. Every cell in your body carries the same genomic information, but it is the epigenome that switches on and off genes to tell the cell to be a skin cell or a muscle cell or even a red blood cell.
Changes in the epigenome can switch on or off genes involved in cell growth or the immune response. For example, in leukaemia epigenetic mutations result in the body producing too many white blood cells, they crowd out the red blood cells and platelets and all those extra white blood cells don’t function correctly. In fact, eight years ago Prof Majeti was responsible for discovering that epigenetic mutations are usually the first hit in a long chain of events that lead to leukaemia.
Working together, Prof Majeti and Dr Thomas will detail the influence certain metabolites have on epigenomic function. Their research and research from others, has shown that you can block certain metabolic enzymes in the body without impacting the function of a healthy cell. Interestingly, healthy cells have the ability to adapt to new energy sources, whereas cancer cells are not always as agile and may stop growing and ultimately die if suddenly given a change in metabolism. These insights have led to the conclusion that cancer patients could benefit from metabolic therapy, but first research needs to uncover which mutations are most sensitive and which particular cell context and treatment pathway to target. Central to the link between metabolism and epigenetics is a small molecule “alpha-ketoglutarate” present naturally inside cells but previously under-appreciated as a critical node for cancer and metabolism.
The funding received from the Leukemia & Lymphoma Society-Snowdome Foundation-Leukaemia Foundation Translational Research Program grant will enable Dr Thomas and Prof Majeti to study changes that occur across the alpha-ketoglutarate pathway in leukaemia cells. By understanding this pathway, they can then identify vulnerabilities in the process that could be targeted by existing pharmacological therapies, designing new pharmacological metabolic treatments optimised for cancer patients and designing precision dietary interventions.