Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulomonocytic differentiation of human hematopoietic progenitors
Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulomonocytic differentiation of human hematopoietic progenitors
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DOI：
10.1182/blood-2010-12-324707
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发表时间：
2011-09-01
期刊：
影响因子：
20.3
通讯作者：
Delhommeau, Francois
中科院分区：
文献类型：
--
作者：
Pronier, Elodie;Almire, Carole;Delhommeau, Francois
TET 2在DNA中将5-甲基胞嘧啶转化为5-羟甲基胞嘧啶（5-hmC），并且在骨髓恶性肿瘤（包括骨髓增生性肿瘤）中经常发生突变。在这里，我们表明，5-hmC的水平降低粒细胞DNA从骨髓增生性肿瘤患者TET 2突变与健康患者相比，粒细胞DNA。RNA干扰抑制TET 2降低人白血病细胞系和脐带血CD 34（+）细胞中5-hmC水平这些结果证实了TET 2在人造血细胞中的酶功能。在脐带血CD 34（+）细胞中TET 2的敲低使祖细胞分化偏向于粒单核细胞谱系，而淋巴样和红系谱系的分化则以牺牲为代价。此外，通过监测体外粒单核细胞的发育，我们发现粒细胞分化减少，单核细胞增加。我们的研究结果表明，TET 2破坏影响5-hmC在人类骨髓细胞的水平，并参与骨髓恶性肿瘤的发病机制，通过髓样分化的障碍。（Blood.2011;118（9）：2551-2555）
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)