A Zebrafish Model of Myelodysplastic Syndrome Produced through tet2 Genomic Editing
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Author
Gjini, Evisa
Mansour, Marc
Sander, Jeffry
Moritz, Nadine
Nguyen, Ashley
Kesarsing, Michiel
Gans, Emma
He, Shuning
Chen, Si
Ko, Myunggon
Kuang, You-Yi
Yang, Song
Zhou, Yi
Rodig, Scott
Zon, Leonard
Joung, J. Keith
Rao, Anjana
Look, A. Thomas
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https://doi.org/10.1128/MCB.00971-14Metadata
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Gjini, Evisa, Marc R. Mansour, Jeffry D. Sander, Nadine Moritz, Ashley T. Nguyen, Michiel Kesarsing, Emma Gans, et al. 2015. “A Zebrafish Model of Myelodysplastic Syndrome Produced through Tet2 Genomic Editing.” Molecular and Cellular Biology 35 (5): 789–804. doi:10.1128/MCB.00971-14.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.Terms of Use
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