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      Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulomonocytic differentiation of human hematopoietic progenitors.

      Blood

      metabolism, 5-Methylcytosine, administration & dosage, RNA, Small Interfering, RNA Interference, physiology, genetics, antagonists & inhibitors, Proto-Oncogene Proteins, Myelopoiesis, Mutation, pathology, Monocytes, Lentivirus, Humans, cytology, Hematopoietic Stem Cells, Granulocytes, Genetic Vectors, Fetal Blood, Erythropoiesis, DNA-Binding Proteins, DNA Methylation, biosynthesis, analogs & derivatives, Cytosine, Colony-Forming Units Assay, Cell Lineage, Cell Line, Tumor

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          Abstract

          TET2 converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA and is frequently mutated in myeloid malignancies, including myeloproliferative neoplasms. Here we show that the level of 5-hmC is decreased in granulocyte DNA from myeloproliferative neoplasm patients with TET2 mutations compared with granulocyte DNA from healthy patients. Inhibition of TET2 by RNA interference decreases 5-hmC levels in both human leukemia cell lines and cord blood CD34(+) cells. These results confirm the enzymatic function of TET2 in human hematopoietic cells. Knockdown of TET2 in cord blood CD34(+) cells skews progenitor differentiation toward the granulomonocytic lineage at the expense of lymphoid and erythroid lineages. In addition, by monitoring in vitro granulomonocytic development we found a decreased granulocytic differentiation and an increase in monocytic cells. Our results indicate that TET2 disruption affects 5-hmC levels in human myeloid cells and participates in the pathogenesis of myeloid malignancies through the disturbance of myeloid differentiation.

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          Author and article information

          Journal
          21734233
          3292425
          10.1182/blood-2010-12-324707

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