title: A zebrafish model of myelodysplastic syndrome produced through tet2 genomic editing.
abstract: The ten-eleven translocation 2 gene (TET2) encodes a member of the TET family of DNA methylcytosine oxidases that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to initiate the demethylation of DNA within genomic CpG islands. Somatic loss-of-function mutations of TET2 are frequently observed in human myelodysplastic syndrome (MDS), which is a clonal malignancy characterized by dysplastic changes of developing blood cell progenitors, leading to ineffective hematopoiesis. We used genome-editing technology to disrupt the zebrafish Tet2 catalytic domain. tet2(m/m) (homozygous for the mutation) zebrafish exhibited normal embryonic and larval hematopoiesis but developed progressive clonal myelodysplasia as they aged, culminating in myelodysplastic syndromes (MDS) at 24 months of age, with dysplasia of myeloid progenitor cells and anemia with abnormal circulating erythrocytes. The resultant tet2(m/m) mutant zebrafish lines show decreased levels of 5hmC in hematopoietic cells of the kidney marrow but not in other cell types, most likely reflecting the ability of other Tet family members to provide this enzymatic activity in nonhematopoietic tissues but not in hematopoietic cells. tet2(m/m) zebrafish are viable and fertile, providing an ideal model to dissect altered pathways in hematopoietic cells and, for small-molecule screens in embryos, to identify compounds with specific activity against tet2 mutant cells.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Evisa
authors.initials: E
authors.lastname: Gjini
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA Department of Hematology, UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Mansour
authors.affiliation: Molecular Pathology Unit, Center for Computational and Integrative Biology, and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, USA Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jeffry D
authors.initials: JD
authors.lastname: Sander
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Moritz
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ashley T
authors.initials: AT
authors.lastname: Nguyen
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michiel
authors.initials: M
authors.lastname: Kesarsing
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Gans
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shuning
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Si
authors.initials: S
authors.lastname: Chen
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Myunggon
authors.initials: M
authors.lastname: Ko
authors.affiliation: Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences No. 232, Daoli District Harbin, Heilongjiang, People's Republic of China.
authors.forename: You-Yi
authors.initials: YY
authors.lastname: Kuang
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Yang
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Rodig
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.affiliation: Molecular Pathology Unit, Center for Computational and Integrative Biology, and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, USA Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: J Keith
authors.initials: JK
authors.lastname: Joung
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA thomas_look@dfci.harvard.edu.
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D002454:Cell Differentiation; D018899:CpG Islands; D004268:DNA-Binding Proteins / Q000378:metabolism; D049308:Dioxygenases / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005838:Genotype; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D017403:In Situ Hybridization; D007668:Kidney / Q000378:metabolism; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D029961:Zebrafish Proteins; C000596889:TET2 protein, zebrafish; D049308:Dioxygenases