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

Blood - Tập 118 - Trang 2551-2555 - 2011
Elodie Pronier1,2, Carole Almire1,3, Hayat Mokrani1,2,4, Aparna Vasanthakumar5, Audrey Simon1,2, Barbara da Costa Reis Monte Mor1,2, Aline Massé1,2, Jean-Pierre Le Couédic1,2, Frédéric Pendino6,7, Bruno Carbonne8, Jérôme Larghero9, Jean-Luc Ravanat10, Nicole Casadevall1,3, Olivier A. Bernard2,11, Nathalie Droin1,2, Eric Solary1,2, Lucy A. Godley5, William Vainchenker1,2, Isabelle Plo1,2, François Delhommeau1,3
1Inserm, U1009, Institut Gustave Roussy, Villejuif, France;
2Université Paris Sud 11, Orsay, France;
3Assistance Publique–Hôpitaux de Paris (AP-HP), Laboratoire d'Hématologie, Hôpital Saint-Antoine, Paris, France;
4Université Paris 6 Pierre et Marie Curie, Paris, France
5Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL
6INSERM U1007, Paris, France
7Université Paris Descartes, Paris, France
8AP-HP, Service de Gynécologie Obstétrique, Hôpital Saint-Antoine, Paris, France;
9Université Paris 7 Diderot, Hôpital Saint Louis, Unité de Thérapie Cellulaire, Paris, France;
10Commissariat à l'Energie Atomique, FRE CNRS 3200, Laboratoire Lésions des Acides Nucléiques, Grenoble, France; and
11Inserm U985, Institut Gustave Roussy, Villejuif, France

Tóm tắt

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.

Tài liệu tham khảo

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