Contribution of the tumour microenvironment to the progression of the myeloid leukemia of Down syndrome: In vivo analysis using a zebrafish-based approach

Approximately 30% of children with Down syndrome will develop a pre-leukemia condition at birth called transient myeloproliferative disease (TMD) that resolves with no treatment. However, 20% of these children will develop acute myeloid leukemia (AML) before the age of 4 years. Factors that affect the environment in which the blood cells are being made, which change from birth through infancy, likely contribute to leukemia development but have been difficult to study. Dr Jason Berman and his team will transplant human Down syndrome TMD and AML cells into see-through zebrafish embryos, which have similar stages of blood development to humans, in order to study previously identified and new factors outside the blood cells to determine the signals that result in leukemia development. Previous studies have shown that TMD cells in children with Down syndrome may disappear or continue to survive and grow based on factors outside these cells called cytokines and growth factors. However, most of these studies have not examined cells directly from patients and have not been able to observe what happens to these cells in a similar microenvironment to children with Down syndrome. The team has developed a zebrafish human cancer cell transplant model that enables the direct visualization of fluorescently labeled cancer cells and components of the microenvironment over time. It is unclear why the TMD that affects 30% of children with Down syndrome spontaneously disappears but recurs in a subset of 20% of children as an aggressive leukemia. As infants grow into children, their blood development shifts from being produced in the fetal liver to the bone marrow. Since TMD and leukemia cells are very similar, it is possible that factors in the site where the blood cells are being formed influence what happens. Researchers will investigate if particular factors made by the fetal liver contribute to development of leukemia from TMD, by injecting cells from patients into transparent zebrafish, which have similar stages of blood development, and observing how the presence of these factors influence the behaviour of the human leukemia cells. By treating these transplanted fish with panels of drugs with known targets and seeing which ones affect cell behaviour, researchers can discover new factors important for leukemia progression. This study will be able to determine which factors outside of the leukemia cells themselves contribute to the progression of TMD in Down syndrome to an aggressive leukemia. By identifying these factors, they may be able to intervene and prevent leukemia development in this disease. While TMD and leukemia are relatively common in children with Down syndrome, it is overall a rare disease. However, this paradigm may also provide clues with implications for other types of leukemia that do not involve spontaneous remission, and how researchers can target the tumour microenvironment to prevent disease progression.