Each day, humans require the production of about one hundred billion new blood cells for proper hematopoietic function. Assaults to the hematopoietic system can cause severe diseases such as leukemias, lymphomas, and anemias. As a lab we are dissecting hematopoietic development and disease using chemical screens, genetic screens, and analysis of novel transgenic lines in zebrafish. In addition we are validating and expanding our findings in mouse, human cell lines, and induced pluripotent cells. There are still many outstanding questions about how hematopoietic progenitor cells are induced from vascular precursors, how hematopoietic stem cells (HSCs) home to and engraft into their stem cell niche, what genes controls stem cell self renewal and differentiation, what goes awry in blood cancers and diseases, and how to improve treatments such as bone marrow transplants. Hematopoiesis is well conserved in the zebrafish, which is a wonderful system for studying all of these processes. Zebrafish lay hundreds of embryos a week, develop red blood cells within 24 hours, and are transparent, which means that we can observe the blood cells as they develop and differentiate. A chemical screen recently found that prostaglandins upregulate blood stem cells, and this drug is now in clinical trial to improve engraftment of HSCs upon bone marrow transplant. Projects in the lab include 1) trying to understand how prostaglandins and other factors enhance HSC production, 2) using novel transgenic lines to visualize HSC engraftment into the niche for the first time, 3) screening for factors that improve HSC engraftment in a transplant model, 4) chemical screening to improve anemic blood cells, and 5) understanding the genetic and epigenetic regulators of all steps of hematopoiesis.
The Zon Lab created the first animal model of a BRAF-driven cancer in 2005 with the publication of our Tg(mitf:BRAFV600E);p53-/- zebrafish melanoma model. Using this model, our lab has gone on to identify an important epigenetic regulator, SETDB1, that is amplified in some human melanomas and which accelerates melanoma onset in our fish and has identified a novel approach to treat melanomas through targeting of their neural crest phenotype by repurposing an FDA-approved drug, leflunomide. Further expanding on these projects, we have ongoing projects focusing on: 1) identifying additional relevant epigenetic regulators of melanoma onset, 2) deconstructing the fundamental mechanisms of leflunomide’s action, 3) monitoring and characterizing in vivo the molecular events governing melanoma initiation at cellular resolution, 4) characterizing mechanisms of melanoma drug resistance, and 5) analyzing mechanisms governing neural crest mobility.