Transgenic zebrafish models of HOXA9- and cMyc-mediated human acute myeloid leukaemia

Acute myeloid leukaemia (AML) is a blood cancer, characterized by the failure of developing white blood cells to mature into functional components of the immune system. The result is an accumulation of immature blood cells that impede normal bodily functions. AML comprises 20% of childhood leukaemia and is the most common leukaemia in adults. Despite advances in therapy, ~40% will die of their disease. Characterizing the underlying molecular events that lead to AML will enable the development of drugs to target the specific defect in leukaemic cells, with better survival and reduced toxicity. The zebrafish is an exciting and promising research tool for studying AML. Notably, they possess similar blood cell types found in humans with the additional advantages of small size, high reproductive capacity and external embryonic development compared with mammals. Zebrafish have successfully been used to model other human leukaemia. We aim to create the first zebrafish model of AML by genetically manipulating animals to overexpress known cancer-related genes. Our focus is on two genes: HOXA9 and CMYC. HOXA9 levels are frequently elevated in AML and portend a poor prognosis, and prevent maturation of developing blood cells by a mechanism that remains poorly defined. CMYC is a potent cancer-causing gene involved in many human tumours, including AML. Mice expressing high levels of cMyc develop AML 100% of the time, but again, the molecular mechanism is unknown. Using well-established genetic techniques, we are generating zebrafish that will express these cancer-causing genes in blood cells and thus develop AML. These living models of human AML can then be easily studied and manipulated from the early stages of life and development, providing new insight into disease progression. Ultimately, these models can be utilized in the rapid screening of new potential drugs to combat the disease, which is not easily accomplished in traditional mouse models of AML.