학술논문
Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulo-monocytic differentiation of human hematopoietic progenitors.
Document Type
Article
Author
Pronier, Elodie; Carole Almire; 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
Source
Subject
*MYELOPROLIFERATIVE neoplasms
*GRANULOCYTES
*GENETIC mutation
*HEMATOPOIETIC growth factors
*BLOOD cells
*PATIENTS
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Language
ISSN
0006-4971
Abstract
TET2 converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA and is frequently mutated in myeloid malignancies, including myeloproliferative neoplasms (MPN). Here we show that the level of 5-hmC is decreased in granulocyte DNA from MPN patients with TET2 mutations, compared to granulocyte DNA from healthy individuals. 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 granulo-monocytic lineage at the expense of lymphoid and erythroid lineages. In addition by monitoring in vitro granulo-monocytic development we find 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 to the pathogenesis of myeloid malignancies through disturbing myeloid differentiation. [ABSTRACT FROM AUTHOR]