title: Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulomonocytic differentiation of human hematopoietic progenitors.
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.
authors: Inserm, U1009, Institut Gustave Roussy, Villejuif, France.
authors: Elodie
authors: E
authors: Pronier
authors: Carole
authors: C
authors: Almire
authors: Hayat
authors: H
authors: Mokrani
authors: Aparna
authors: A
authors: Vasanthakumar
authors: Audrey
authors: A
authors: Simon
authors: Barbara
authors: B
authors: da Costa Reis Monte Mor
authors: Aline
authors: A
authors: Massé
authors: Jean-Pierre
authors: JP
authors: Le Couédic
authors: Frédéric
authors: F
authors: Pendino
authors: Bruno
authors: B
authors: Carbonne
authors: Jérôme
authors: J
authors: Larghero
authors: Jean-Luc
authors: JL
authors: Ravanat
authors: Nicole
authors: N
authors: Casadevall
authors: Olivier A
authors: OA
authors: Bernard
authors: Nathalie
authors: N
authors: Droin
authors: Eric
authors: E
authors: Solary
authors: Lucy A
authors: LA
authors: Godley
authors: William
authors: W
authors: Vainchenker
authors: Isabelle
authors: I
authors: Plo
authors: François
authors: F
authors: Delhommeau
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism* / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D019070:Cell Lineage; D003114:Colony-Forming Units Assay; D003596:Cytosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D049308:Dioxygenases; D004920:Erythropoiesis / Q000235:genetics* / Q000502:physiology; D005312:Fetal Blood / Q000166:cytology; D005822:Genetic Vectors / Q000235:genetics; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D038042:Myelopoiesis / Q000235:genetics* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D049308:Dioxygenases; C541081:TET2 protein, human