The JAK/STAT pathway regulates multiple biological processes and is conserved from Drosophila to humans. A gain of function mutation in the human JAK2 gene (JAK2V617F) is a causative mutation in myeloproliferative neoplasms patients (MPNs), which are characterized by the increased production of myeloid lineage blood cells and for which there is no curative therapy. The Drosophila JAK/STAT pathway is more straightforward than its mammalian counterpart, with only one JAK tyrosine kinase, Hopscotch (Hop), and one STAT transcription factor, Stat92E. A dominant active mutation in hop (hopTumurous-lethal , hopTum) increases the number of myeloid lineage cells, parallel to patients harboring the JAK2 V617F mutation. The expansion of the myeloid lineage in hopTum mutants result in tumors that can be suppressed by heterozygosity for Stat92E. Based on this observation, we devised a genetic deficiency screen to identify genes that modify the hopTum tumor phenotype. We report 35 enhancer and 11 suppressor deficiencies that significantly modify the hop Tum tumor burden.
In this work, we characterize three strong enhancer modifiers. First, we present deficiencies uncovering the Hippo pathway genes expanded (ex) and warts (wts) significantly enhance the hopTum tumor burden. Hippo signaling restrains the transcriptional co-activator Yorkie (Yki) to the cytoplasm and inhibits transcription of Yki target genes. We establish that elevated Yki signaling promotes proliferation of hemocytes, which become tumors because of elevated JAK/STAT signaling in the hopTum background. Finally, show that Enhancer of Polycomb (E(Pc)), through the Tip60 complex, regulates the hopTum tumor phenotype. E(Pc) is an essential, non-catalytic component of the Tip60 lysine acetyltransferase. Through genetic and biochemical experiments, we conclude that E(Pc) through the Tip60 complex downregulates JAK/STAT signaling by regulating the protein expression of Hop. Overall, our findings demonstrate that Drosophila is a powerful tool in cancer research.
|Advisor:||Bach, Erika A.|
|Commitee:||Govind, Shubha, Levy, David, Nance, Jeremy, Rushlow, Christine|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 80/08(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Genetics, Physiology, Developmental biology|
|Keywords:||Drosophila, Hematopoiesis, Hippo pathway, Jak/stat pathway, Myeloproliferative neoplasms, Tip60 complex|
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