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

Author:

Pronier Elodie12,Almire Carole1234,Mokrani Hayat12,Vasanthakumar Aparna5,Simon Audrey12,da Costa Reis Monte Mor Barbara12,Massé Aline12,Le Couédic Jean-Pierre12,Pendino Frédéric67,Carbonne Bruno8,Larghero Jérôme9,Ravanat Jean-Luc10,Casadevall Nicole1234,Bernard Olivier A.211,Droin Nathalie12,Solary Eric12,Godley Lucy A.5,Vainchenker William12,Plo Isabelle12,Delhommeau François1234

Affiliation:

1. Inserm, U1009, Institut Gustave Roussy, Villejuif, France;

2. Université Paris Sud 11, Orsay, France;

3. Université Paris 6 Pierre et Marie Curie, Paris, France;

4. Assistance Publique–Hôpitaux de Paris (AP-HP), Laboratoire d'Hématologie, Hôpital Saint-Antoine, Paris, France;

5. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL;

6. Inserm, U1007, Paris, France;

7. Université Paris-Descartes, Paris, France;

8. AP-HP, Service de Gynécologie Obstétrique, Hôpital Saint-Antoine, Paris, France;

9. Université Paris 7 Diderot, Hôpital Saint Louis, Unité de Thérapie Cellulaire, Paris, France;

10. Commissariat à l'Energie Atomique, FRE CNRS 3200, Laboratoire Lésions des Acides Nucléiques, Grenoble, France; and

11. Inserm, U985, Institut Gustave Roussy, Villejuif, France

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3