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

2011; Elsevier BV; Volume: 118; Issue: 9 Linguagem: Inglês

10.1182/blood-2010-12-324707

1528-0020

Elodie Pronier, Carole Almire, Hayat Mokrani, Aparna Vasanthakumar, Audrey Simon, Bárbara da Costa Reis Monte-Mór, Aline Massé, Jean‐Pierre Le Couedic, Frédéric Pendino, B. Carbonne, Jérôme Larghero, Jean‐Luc Ravanat, Nicole Casadevall, Olivier Bernard, Nathalie Droin, Éric Solary, Lucy A. Godley, William Vainchenker, Isabelle Plo, François Delhommeau,

Hemoglobinopathies and Related Disorders

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.