Leukaemia is the most common cancer diagnosed in children, and is second only to brain cancer in terms of the deaths it causes. To improve survival, we need to improve our understanding of leukaemia and how it can best be targeted.
Subtypes of leukaemia
The two main types of leukaemia diagnosed in children are acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). But within these, there are at least 20 different subtypes. Some of these subtypes are particularly aggressive and difficult to treat, hence are called ‘high-risk’ leukaemias. One such leukaemia is T-ALL, which specifically affects a type of white blood cell called T lymphocytes (T-cells).
“Because children with T-ALL often have poor outcomes, they are given very intensive treatment,” explains Dr Charley de Bock, Team Leader in our Blood Cancers theme. “This means high-dose chemotherapy, which often causes serious long-term side effects. What we really need is a new way to treat T-ALL, which is much safer as well as more effective.”
Understanding what drives leukaemia
To understand what drives the development of T-ALL, Charley is looking at leukaemic cells on a molecular level and investigating the genetic mutations or aberrations involved. Although a fair bit is now known about individual genetic mutations in ALL, it is not yet understood how these mutations interact and work together to drive the disease.
“To treat high-risk ALL successfully, we really need to understand the functional relationship between multiple co-occurring mutations,” he explains. “That way, we can design combination therapies capable of attacking the disease on all fronts simultaneously.”
Targeting T-ALL
In research recently published in the journal Nature Communications, Charley has made important progress in understanding how T-ALL might best be treated. Using an approach known as ‘functional genomics’ – modelling how different genes and proteins interact to drive the development of disease − he has found a combination of gene-related factors that interact to drive T-ALL in a certain subset of patients.
Past research has shown that children with a particular chromosomal rearrangement (TCF7-SPI1 gene fusions) represent a distinct subgroup of T-ALL, and that these children tend to do very poorly, with significantly shorter survival times. In his new research, Charley used highly specialised mouse models to show that these gene fusions often interact with a genetic mutation known as NRAS, and that this ‘oncogenic cooperation’ leads to the development of aggressive T-cell leukaemia.
Better still, he found that this interaction could be pharmacologically targeted, effectively cancelling out its cancer-causing activity. Further research will reveal whether identifying this potential Achilles’ heel of T-ALL leads the way to a new treatment for this disease. We certainly hope so.
