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Ko, Myunggon
Molecular Immunology & Cancer Epigenetics
Research Interests
  • TET proteins, DNA hydroxymethylation, oncogenesis, cancer stem cells, cancer therapy

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A zebrafish model of myelodysplasia produced through tet2 genomic editing

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Title
A zebrafish model of myelodysplasia produced through tet2 genomic editing
Author
Gjini, EvisaMansour, Marc RSander, Jeffry DMoritz, NadineNguyen, Ashley TKesarsing, MichielGans, EmmaHe, ShuningChen, SiKo, MyunggonKuang, You-YiYang, SongZhou, YiRodig ScottZon, Leonard IJoung, J.KeithRao, AnjanaLook, Thomas
Keywords
ACUTE MYELOID-LEUKEMIA; HEMATOPOIETIC STEM-CELLS; MUTANT TET2; IN-VIVO; MUTATIONS; DNA; DIFFERENTIATION; MALIGNANCIES; TRANSPLANTATION; MYELOFIBROSIS
Issue Date
2015-03
Publisher
AMER SOC MICROBIOLOGY
Citation
MOLECULAR AND CELLULAR BIOLOGY, v.35, no.5, pp.789 - 804
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. tet2m/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 tet2m/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. tet2m/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.
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DOI
10.1128/MCB.00971-14
ISSN
0270-7306
Appears in Collections:
PHY_Journal Papers
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