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

Elodie Pronier, Carole Almire, Hayat Mokrani, Aparna Vasanthakumar, Audrey Simon, Barbara Da Costa Reis Monte Mor, Aline Massé, Jean Pierre Le Couédic, Frédéric Pendino, Bruno Carbonne, Jérôme Larghero, Jean Luc Ravanat, Nicole Casadevall, Olivier A. Bernard, Nathalie Droin, Eric Solary, Lucy A. Godley, William Vainchenker, Isabelle Plo, François Delhommeau*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

155 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2551-2555
Number of pages5
JournalBlood
Volume118
Issue number9
DOIs
StatePublished - Sep 1 2011

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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