Tumour suppressor networks: the role of SHIP-1 and Lyn in suppressing haematopoietic tumours

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Haematopoietic malignancies kill a large number of Australians each year. Improving our understanding of the molecular mechanisms that underlie these diseases is essential for the design of more effective treatments. Lyn and SHIP-1 are enzymes that are found in blood cells, and both participate in terminating cellular responses. As such, these enzymes are critically important for maintaining stability in the immune system. While these enzymes have unique roles, we also have good evidence that in some instances Lyn and SHIP-1 participate in the same biochemical pathway. We have created mice that are unable to make Lyn protein, and have found that these mice develop blood cell tumours. Mice lacking SHIP-1 develop a number of haematological defects, but die at a young age due to an inflammatory lung condition, making an assessment of the role of SHIP-1 in age-dependent tumour development difficult. We now wish to study the role of SHIP-1 in tumour development, by generating mice that lack SHIP-1 in specific white blood cell compartments. We are also investigating how SHIP-1 and Lyn cooperate in tumour suppression, and we have recently generated mice that simultaneously lack both SHIP-1 and Lyn. Preliminary studies indicate that compound mutant mice develop multiple haematological malignancies. We will fully characterize tumour development in these animals, and determine the molecular basis for this pathology. We will focus on two pathways that have been previously implicated in oncogenesis. These studies will improve our insight into how Lyn and SHIP-1 cooperate in blood cell development, cellular homeostasis and oncogenesis, and add to our biological and biochemical understanding of tumour suppressor networks.