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Pronier, Elodie; Almire, Carole; Mokrani, Hayat; Vasanthakumar, Aparna; Simon, Audrey; da Costa Reis Monte Mor, Barbara; Massé, Aline; Le Couédic, Jean-Pierre; Pendino, Frédéric; Carbonne, Bruno; Larghero, Jérôme; Ravanat, Jean-Luc; Casadevall, Nicole; Bernard, Olivier A.; Droin, Nathalie; Solary, Eric; Godley, Lucy A.; Vainchenker, William; Plo, Isabelle; Delhommeau, François
Blood, 09/2011, Letnik: 118, Številka: 9Journal Article
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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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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