Identifying a deadly combination of mutations
Exploring how additional genetic changes acquired during a person’s lifetime can work alongside inherited changes to drive AML, Dr Loke is hoping to identify which combinations of mutations are most harmful.
Dr Justin Loke at the University of Manchester is investigating inherited changes in the RUNX1 gene and how these may contribute to the development of leukaemia. His research is also exploring how additional genetic changes acquired during a person’s lifetime can work alongside inherited changes to drive disease. By identifying which combinations of mutations are most harmful, he hopes to better understand what causes leukaemia to develop and progress.
The Challenge:
Some people inherit changes in a gene called RUNX1, which increases their risk of developing serious blood cancers, including myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). In the blood-forming cells of the bone marrow, the RUNX1 gene encodes for the RUNX1 protein, which is a type of protein called a transcription factor. Working to switch other genes on or off, RUNX1 and other transcription factors normally help to regulate the complex process by which the right types of blood cell develop in the right way. But sometimes this can go wrong.
Not everyone with a RUNX1 mutation develops cancer, but certain mutations can increase a person’s lifetime risk. Researchers believe that additional genetic changes acquired during a person’s lifetime help to drive the disease, but it is not yet fully understood which combinations of changes are negative.
The Research:
One such rare inherited condition that affects blood cells, particularly platelets, is RUNX1 familial platelet disorder (RUNX1-FPD). Around one-third of people with RUNX1-FPD develop blood cancers such as MDS or AML. There are currently no personalised treatments for RUNX1-FPD, and for those who develop blood cancer, long-term survival may depend on a stem cell transplant, which can carry significant risks.
Focusing on RUNX1-FPD, Dr Loke has developed laboratory models that recreate how inherited changes in the RUNX1 gene, together with other genetic changes acquired over time, can lead to leukaemia.
More simply put, these models allow Dr Loke to switch off certain genes at the same time in the blood-forming stem cells. He will then use this information to discover which combinations of genetic changes turn healthy blood cells into leukaemia and what changes inside the cells as the disease develops.
The project will create improved laboratory models of RUNX1-related MDS and AML that more closely reflect what happens in patients. These models will allow researchers to study how the disease develops, test potential new treatments and identify promising targets for future therapies.
Project information
What difference will this research make?
This project will help researchers better understand why blood cancers develop in people with RUNX1-FPD and identify the genetic changes that drive them. By creating improved laboratory models that more closely reflect what happens in patients, the research will provide a powerful way to test new treatments and discover more targeted, effective therapies.
In the long term, this could lead to safer, more personalised treatment options for people with inherited forms of blood cancer, improving outcomes and reducing the need for intensive treatments such as stem cell transplantation.