DF/HCC Program Affiliation

Cutaneous Oncology and Melanoma
Leukemia
Cancer Genetics
Cancer Cell Biology

Research Abstract

Research Contributions:
Our laboratory focuses on the developmental biology of hematopoiesis and cancer. Over the past five years, we have collected over 30 mutants affecting the hematopoietic system. Some of the mutants represent excellent animal models of human disease. For instance, the isolation of the ferroportin iron transporter was based on a mutant zebrafish and subsequently was shown to be mutated in patients with iron overload disorders. The mutants also represent interesting key regulatory steps in the development of stem cells. Recently, a mutant was found that lacked blood stem cells and the mutated gene proved to be a caudal related homeoprotein called, CDX4. A Cdx-hox pathway was found to participate in early hematopoietic stem cell development, and overexpression of CDX4 leads to ectopic blood development within the zebrafish embryo and in mouse embryonic stem cells. We recently have developed hematopoietic cell transplantation for the zebrafish using blood cells labeled with green fluorescent protein and DSred. We were able to image the hematopoietic cells as they migrate to the marrow and to the thymus.

The laboratory has also developed zebrafish models of cancer. A screen for cell cycle mutants found 19 mutants. Some of these mutants get cancer at a very high rate as heterozygotes based on a carcinogenesis assay. The mutant genes appear to be new cancer genes and we have used small molecules in a chemical suppressor gene to find chemicals that bypass the mutant cell cycle problem. We also have generated a melanoma model in the zebrafish system using transgenics. Transgenic fish get nevi, and in a combination with a p53 mutant fish develop melanomas.

Publications

• Le X, Langenau DM, Keefe MD, Kutok JL, Neuberg DS, Zon LI.Heat shock-inducible Cre/Lox approaches to induce diverse types of tumors and hyperplasia in transgenic zebrafish.Proc Natl Acad Sci U S A 2007 May 21.
  17517602
• Trede NS, Medenbach J, Damianov A, Hung LH, Weber GJ, Paw BH, Zhou Y, Hersey C, Zapata A, Keefe M, Barut BA, Stuart AB, Katz T, Amemiya CT, Zon LI, Bindereif A.Network of coregulated spliceosome components revealed by zebrafish mutant in recycling factor
  17416673
• Steffen LS, Guyon JR, Vogel ED, Beltre R, Pusack TJ, Zhou Y, Zon LI, Kunkel LM.Zebrafish orthologs of human muscular dystrophy genes.BMC Genomics 2007;8:79.
  17374169
• Hultman KA, Bahary N, Zon LI, Johnson SL.Gene Duplication of the zebrafish kit ligand and partitioning of melanocyte development functions to kit ligand a.PLoS Genet 2007 Jan 26;3(1):e17.
  17257055
• Shepard JL, Amatruda JF, Finkelstein D, Ziai J, Finley KR, Stern HM, Chiang K, Hersey C, Barut B, Freeman JL, Lee C, Glickman JN, Kutok JL, Aster JC, Zon LI.A mutation in separase causes genome instability and increased susceptibility to epithelial cancer
  17210788
• Murphey RD, Stern HM, Straub CT, Zon LI.A chemical genetic screen for cell cycle inhibitors in zebrafish embryos.Chem Biol Drug Des 2006 Oct;68(4):213-9.
  17105485
• Bansal D, Scholl C, Fröhling S, McDowell E, Lee BH, Döhner K, Ernst P, Davidson AJ, Daley GQ, Zon LI, Gilliland DG, Huntly BJ.Cdx4 dysregulates Hox gene expression and generates acute myeloid leukemia alone and in cooperation with Meis1a in a murine model
  17068127
• Hu G, Tang J, Zhang B, Lin Y, Hanai J, Galloway J, Bedell V, Bahary N, Han Z, Ramchandran R, Thisse B, Thisse C, Zon LI, Sukhatme VP.A novel endothelial-specific heat shock protein HspA12B is required in both zebrafish development and endothelial function
  16968741
• Murphey RD, Zon LI.Small molecule screening in the zebrafish.Methods 2006 Jul 28.
  16877005
• Gupta S, Zhu H, Zon LI, Evans T.BMP signaling restricts hemato-vascular development from lateral mesoderm during somitogenesis.Development 2006 Jun;133(11):2177-87.
  16672337
• Shaw GC, Cope JJ, Li L, Corson K, Hersey C, Ackermann GE, Gwynn B, Lambert AJ, Wingert RA, Traver D, Trede NS, Barut BA, Zhou Y, Minet E, Donovan A, Brownlie A, Balzan R, Weiss MJ, Peters LL, Kaplan J, Zon LI, Paw BH.Mitoferrin is essential for erythroid
  16511496
• Davidson AJ, Zon LI.The caudal-related homeobox genes cdx1a and cdx4 act redundantly to regulate hox gene expression and the formation of putative hematopoietic stem cells during zebrafish embryogenesis.Dev Biol 2006 Apr 15;292(2):506-18.
  16457800
• Stern HM, Murphey RD, Shepard JL, Amatruda JF, Straub CT, Pfaff KL, Weber G, Tallarico JA, King RW, Zon LI.Small molecules that delay S phase suppress a zebrafish bmyb mutant.Nat Chem Biol 2005 Dec;1(7):366-70.
  16372403
• Gardiner MR, Daggett DF, Zon LI, Perkins AC.Zebrafish KLF4 is essential for anterior mesendoderm/pre-polster differentiation and hatching.Dev Dyn 2005 Dec;234(4):992-6.
  16222715
• Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, Andrews NC.The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis.Cell Metab 2005 Mar;1(3):191-200.
  16054062