Leonard Zon's laboratory focuses on the use of the zebrafish model for research into hematopoiesis and as a screen for oncogenic genes and proteins.
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:
- Identifying additional relevant epigenetic regulators of melanoma onset
- Deconstructing the fundamental mechanisms of leflunomide’s action
- Monitoring and characterizing in vivo the molecular events governing melanoma initiation at cellular resolution
- Characterizing mechanisms of melanoma drug resistance
- Analyzing mechanisms governing neural crest mobility
About Leonard Zon
Leonard Zon, MD is internationally recognized for his pioneering work in stem cell biology and cancer genetics. He has been the preeminent figure in establishing zebrafish as an invaluable genetic model for the study of disease, focusing on blood and cancer development. Dr. Zon pioneered the field of developmental hematopoiesis. He undertook the first genetic screen to find zebrafish mutants with defects in blood formation during embryogenesis. He discovered ferroportin, an iron transporter in the yolk sac of the zebrafish. Ferroportin is also the mammalian placental and duodenal iron transporter. This gene is mutated in hemochromatosis (the first successful prediction of a human disease gene from zebrafish). Dr. Zon studied stem cell biology in zebrafish and discovered that prostaglandins stimulate blood stem cells in embryos and aids stem cell transplantation in fish and mice. PGE2 is in a phase II clinical trial based on this discovery. Dr. Zon developed the zebrafish as a cancer model. Using fish melanoma as an assay system, he identified the causative gene on chromosome 1 that is amplified in human melanoma, found that DHODH inhibitors suppress melanoma (being tested in a clinical trial), and visualized melanoma when initiates as a single cell in vivo. Dr. Zon led the zebrafish community in establishing the NIH Zebrafish Genome Initiative and started the Zebrafish Disease Model Society. As President of the International Society for Stem Cell Research, a society that he started, Dr. Zon has had a major impact on the country’s view of stem cell research.
- Kaufman CK, Mosimann C, Fan ZP, Yang S, Thomas AJ, Ablain J, Tan JL, Fogley RD, van Rooijen E, Hagedorn EJ, Ciarlo C, White RM, Matos DA, Puller AC, Santoriello C, Liao EC, Young RA, Zon LI. A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation. Science. 2016 Jan 29;351(6272):aad2197. PMID: 26823433
- Tamplin OJ, Durand EM, Carr LA, Childs SJ, Hagedorn EJ, Li P, Yzaguirre AD, Speck NA, Zon LI. Hematopoietic stem cell arrival triggers dynamic remodeling of the perivascular niche. Cell. 2015 Jan 15;160(1-2):241-52. PMID:25594182
Li P, Lahvic JL, Binder V, Pugach EK, Riley EB, Tamplin OJ, Panigrahy D, Bowman TV, Barrett FG, Heffner GC, McKinney-Freeman S, Schlaeger TM, Daley GQ, Zeldin DC, Zon LI. Epoxyeicosatrienoic acids enhance hematopoietic stem and progenitor cell engraftment. Nature. 2015 Jul 22;523(7561):468-71. PMID: 26201599
Xu C, Tabebordbar M, Lovino S, Ciarlo C, Liu J, Castiglioni A, Price E, Kahn RC, Wagers AJ, and Zon LI. A zebrafish embryo culture system defines factors that promote vertebrate myogenesis across species. Cell, 2013, Nov 7;155(4):909-21. PMCID: PMC3902670
Ceol CJ, Houvras Y, Jane-Valbuena J, Bilodeau S, Orlando DA, Battisti V, Fritsch L, Lin WM, Hollmann TJ, Ferre F, Bourque C, Burke C, Turner L, Uong A, Johnson LA, Beroukhim R, Mermel CH, Loda M, Slimane A-S-A, Garraway L, Young RA, and Zon LI. The SETDB1 histone methyltransferase is recurrently amplified in and accelerates melanoma. Nature, 2011, Mar 24:471, 513-517. PMCID: PMC3348545
White RM, Cech J, Ratanasirintrawoot S, Lin CY, Rahls PB, Burke CJ, Langdon E, Tomlinson ML, Mosher J, Kaufman C, Chen F, Long HK, Kramer M, Datta S, Neuberg D, Granter S, Young RA, Morrison S, Wheeler GN, and Zon LI. DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature. 2011, Mar 24:471, 518-522. PMCID:PMC3759979
Trompouki E, Bowman TV, Lawton LN, Fan ZP, Wu D-C, DiBiase A, Martin CS, Cech JN, Sessa AK, Leblanc JL, Li P, Durand E, Mosimann C, Heffner GC, Daley GQ, Paulson RF, Young RA and Zon LI. Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration. Cell, 2011, October 28:147 (3);577-589. PMCID: PMC3219441
Bai X, Kim J, Yang Z, Jurynec M, Lee J, LeBlanc J, Sessa A, Jiang H, Grunwald DJ, Lin S, Orkin SH, Zon LI. TIF1γ controls erythroid cell fate by regulating transcriptional elongation. Cell, 2010, Jul 9;142(1):133-143. PMCID: PMC3072682
Goessling W, North TE, Loewer S, Lord AM, Lee S, Stick-Cooper CL, Weidinger G, Puder M, Daley GQ, Moon RT, and Zon LI. Genetic interaction of PGE2 and wnt signaling regulates developmental specification of stem cells and regeneration. Cell, 2009 Mar 20;136(6):1136-46. PMCID:PMC2692708
North TE, Goessling W, Peeters M, Li P, Ceol C, Lord AM, Weber GJ, Harris J, Cutting CC, Huang P, Dzierzak E, and Zon LI. Hematopoietic stem cell development is dependent on blood flow. Cell, 2009, May 15;137(4):736-748. PMCID:PMC2722870
North TE, Goessling W, Walkley CR, Lengerke C, Kopani KR, Lord AM, Weber G, Bowman TV, Jang IH, Grosser T, FitzGerald GA, Daley GQ, Orkin SH, and Zon LI. Prostaglandin E2 regulates vertebrate hematopoietic stem cell homeostasis. Nature, 2007, Jun 21;447(7147):1007-11. PMCID: PMC2775137
Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, Law TC, Brugnara C, Lux SE, Pinkus GS, Pinkus JL, Kingsley PD, Palis J, Fleming MD, Andrews NC, and Zon LI. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature, 2000.