Developmental origins of childhood leukaemia

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.

Many childhood leukaemias originate in utero, suggesting cellular, molecular and epigenetic features of human fetal cells make them particularly susceptible to leukaemic transformation. Human haematopoiesis is a dynamic process that starts in utero. In past and ongoing work we are systematically characterising ontogeny-related properties of human haematopoietic stem and progenitor cells (HSPC), with a particular focus on B lymphopoiesis, and have developed a model of infant ALL by transforming primary human fetal HSPC. The developmental stage-specific cellular and molecular characteristics of fetal and postnatal progenitors are likely to determine the biology of ALL at different ages. Developing leukaemia models using primary human HSPC through ontogeny, will enable us to unravel the mechanisms that initiate and maintain ALL. Our studies feed into translational research projects including developing novel immunotherapies and small molecule inhibitors; and
molecular profiling of patient samples via national and international infant ALL trials.

I hypothesise that identification of key developmental stage- or leukaemia-specific mechanisms will allow these to
be targeted for treatment. The overarching aim of my research is to improve the outcomes of children with high risk ALL using these strategies.

Specific Aims:
1. How does human haematopoiesis evolve from embryonic life through to adulthood? Pinpointing the molecular basis of embryonic/fetal specific B lymphoid development in humans using functional,
transcriptomic and chromatin accessibility assays.
2. How does the developmental stage at which a leukaemia initiates affect the biology of the disease? To investigate whether developmental stage-specific characteristics of human HSPC determine the biology of poor prognosis ALL, we will develop models of high-risk childhood leukaemia (TCF3-HLF+; BCR-ABL1+ and BCR-ABL-‘like’ ALL) by transforming fetal and postnatal HSPC using CRISPR based approaches. These models will be characterised using functional and molecular assays.
3. What are the mechanisms that drive treatment-resistant leukaemias? Our leukaemia models allow direct comparison of cell populations pre- and post-transformation in humans, enabling key dependencies required for leukaemia initiation and progression to be identified. We will investigate molecular mechanisms using transcriptomic, genomic and epigenetic techniques, including at single cell level.
4. Can we leverage this knowledge to develop more effective therapy? The leukaemia models will be taken forward for preclinical studies to identify pan-leukaemic/cancer targets, as well as key developmental stage-specific targets that can transform outcomes in treatment-refractory leukaemias. Commercialisation pipelines developed through Deep Blue Therapeutics (collaboration T Milne), will be made available for any new therapeutic targets identified.

Clinical:
i) Co-PI on national infant ALL study;
ii) developing an adapted protocol for treatment of infant ALL in India (funded by Wellcome Trust),
iii) incorporating scientific studies as part of a consortium for the upcoming international infant ALL study.