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

被引：145

作者：

Pronier, Elodie ^{[2
,3
]}

Almire, Carole ^{[1
,2
,3
,4
]}

Mokrani, Hayat ^{[2
,3
]}

Vasanthakumar, Aparna ^{[5
]}

Simon, Audrey ^{[2
,3
]}

Mor, Barbara da Costa Reis Monte ^{[2
,3
]}

Masse, Aline ^{[2
,3
]}

Le Couedic, Jean-Pierre ^{[2
,3
]}

Pendino, Frederic ^{[6
,7
]}

Carbonne, Bruno ^{[8
]}

Larghero, Jerome ^{[9
]}

Ravanat, Jean-Luc ^{[10
]}

Casadevall, Nicole ^{[1
,2
,3
,4
]}

Bernard, Olivier A. ^{[3
,11
]}

Droin, Nathalie ^{[2
,3
]}

Solary, Eric ^{[2
,3
]}

Godley, Lucy A. ^{[5
]}

Vainchenker, William ^{[2
,3
]}

Plo, Isabelle ^{[2
,3
]}

Delhommeau, Francois ^{[1
,2
,3
,4
]}

机构：

[1] Hop St Antoine, AP HP, Hematol Lab, F-75012 Paris, France

[2] Inst Gustave Roussy, INSERM, U1009, F-94805 Villejuif, France

[3] Univ Paris 11, Orsay, France

[4] Univ Paris 06, Paris, France

[5] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA

[6] INSERM, U1007, Paris, France

[7] Univ Paris 05, Paris, France

[8] Hop St Antoine, AP HP, Serv Gynecol Obstet, F-75012 Paris, France

[9] Univ Paris 07, Hop St Louis, Unite Therapie Cellulaire, Paris, France

[10] Commissariat Energie Atom, FRE CNRS 3200, Lab Les Acides Nucle, Grenoble, France

[11] Inst Gustave Roussy, INSERM, U985, F-94805 Villejuif, France

来源：

BLOOD | 2011年 / 118卷 / 09期

关键词：

CHRONIC MYELOMONOCYTIC LEUKEMIA; MYELOID MALIGNANCIES; MYELOPROLIFERATIVE NEOPLASMS; POLYCYTHEMIA-VERA; DNA METHYLATION; TET2; MUTATIONS; MUTANT TET2; JAK2; CELLS; FREQUENT;

D O I：

10.1182/blood-2010-12-324707

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. (Blood.2011;118(9):2551-2555)

引用

页码：2551 / 2555

页数：5

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