Drosophila as a low complexity model for human neoplasms

New York University School Of Medicine, New York NY

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Abstract

? DESCRIPTION (provided by applicant): The JAK/STAT signaling pathway is required for multiple processes in mammalian development; dysregulation of this pathway has been identified in many cancers, including a group of hematopoietic disorders called myeloproliferative neoplasms (MPNs). While therapies for MPNs have been developed, most treat only the symptoms and do not successfully cure the disease or extend lifespan. Moreover, many patients develop resistance to clinical drug regimens and experience negative side effects, such as anemia. Given the inefficacy of existing treatments, it is important to identify novel therapeutic targets. The mammalian JAK/STAT pathway is conserved in the fruit fly, Drosophila, but is much less complex. Hyperactive mutations in the Drosophila JAK have been identified, which result in an increased number of blood cells, similar to MPNs in humans. Blood cells will aggregate and be melanized, referred to as melanotic tumors. We have conducted a genetic screen for novel modifiers of JAK/STAT signaling using this hyperactive JAK mutant and have identified the inositol polyphosphate kinase, Ipk2, as a putative positive regulator of JAK/STAT signaling. Since very little is known about Ipk2, the aim of this project is to characterize the role of Ipk2 in JAK/STAT-mediated melanotic tumor formation. Using molecular techniques, I will identify at what level Ipk2 acts in JAK/STAT signaling. I will use immunohistochemistry to determine if Ipk2 functions in hematopoiesis. Finally, dysregulation of other signaling pathways has also been shown to cause melanotic tumor formation, as seen with JAK/STAT signaling, which raises the question of how broadly Ipk2 might be involved in this process. I plan to use genetic techniques to determine if Ipk2 is required for melanotic tumor formation induced by the hyperactivation of other signaling pathways. We expect that the results from this project should be relevant to human MPNs and will suggest novel therapeutic targets for JAK/STAT-related disorders.