Nine out of ten children with the most common childhood leukaemia can now be cured, but the remaining ten percent carry genetic abnormalities that make their disease resist treatment. This project builds laboratory models of those high-risk leukaemias by inserting faulty MLL genes into normal blood cells, transforming them into cancer cells that behave exactly like the aggressive human disease. The researchers will then use these models—alongside patient samples—to identify which genes are mistakenly switched on or off in treatment-resistant cells, and test whether suppressing those pathways can make the leukaemia less aggressive. If successful, the work could reveal molecular "labels" unique to resistant leukaemia cells, enabling development of drugs that target only those cells while sparing healthy tissue. This is fundamental science: the immediate goal is understanding how these leukaemias develop and why they resist therapy, not delivering a new treatment tomorrow. But similar mechanistic studies of childhood leukaemia have already transformed survival rates from near-zero to 90 percent, and the same approach could now crack the remaining hard cases.
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Although it is possible to cure 90% of children with the commonest type of blood cancer (leukaemia), unfortunately there are some children who develop leukaemia who cannot be cured. These are called 'high-risk' leukaemias and are usually associated with abnormalities of particular genes. A better understanding of these treatment resistant leukaemias is required, so that we can cure every child with leukaemia. We have developed a model of infant leukaemia by creating an MLL leukaemia gene in normal cells so that those cells behave just like infant leukaemia. We now want to create similar models for other high-risk childhood leukaemias by transforming normal cells. We will use these models to understand how these leukaemias develop, the pathways that drive aggressive disease and test new drugs for treatment. Previous research in our lab has shown that in some cases, leukaemic cells depend on genes that are turned on or off by mistake. In this project, we want to use leukaemia cells from the models we develop, and from patients to understand how these genes contributes to their ability to resist treatment. To do this we will analyse how normal cells change during and after transformation, and whether suppressing these pathways can make the leukaemia less aggressive. The results of these experiments will inform us whether we can use certain targets to develop novel effective treatments, particularly by targeting it as a ‘label’ unique to treatment-resistant leukaemia cells.
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