Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2.
Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2.
复制标题
作者：
TET2是TET1的近亲，TET1是一种将DNA中的5-甲基胞嘧啶（5-mC）转化为5-羟甲基胞嘧啶（5-hmC）的酶。编码TET2的基因位于染色体4q24，在不同髓系恶性肿瘤患者中显示复发性微缺失和拷贝中性杂合性缺失（CN-LOH）的区域。体细胞TET2突变常见于骨髓增生异常综合征（MDS）、骨髓增生性肿瘤（MPN）、MDS/MPN重叠综合征，包括慢性髓细胞白血病（CMML）、急性髓系白血病（AML）和继发性AML （sAML）。我们在这里表明，与髓系恶性肿瘤相关的TET2突变损害了TET2的催化活性。与健康对照者的骨髓样本相比，TET2突变患者的骨髓样本在基因组DNA中显示出一致的低水平5-hmC。此外，在小鼠造血前体细胞中，小发夹RNA （shRNA）介导的Tet2缺失使其向单核细胞/巨噬细胞谱系分化。来自高5-hmC患者的骨髓样本与健康对照组之间的DNA甲基化没有显著差异，但来自低5-hmC患者的样本在大多数差异甲基化的CpG位点上显示出相对于对照组的低甲基化。我们的研究结果表明，TET2对正常的骨髓形成很重要，并表明TET2酶活性的破坏有利于髓系肿瘤的发生。髓系恶性肿瘤中5-hmC水平的测量可能被证明是一种有价值的诊断和预后工具，可用于定制治疗和评估对抗癌药物的反应。
TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukemia (CMML), acute myeloid leukemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise TET2 catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5-hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5-hmC versus healthy controls, but samples from patients with low 5-hmC showed hypomethylation relative to controls at the majority of differentially-methylated CpG sites. Our results demonstrate that TET2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5-hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anti-cancer drugs.
登录
查看更多内容
影响因子：
30.8
作者：
Langemeijer, Saskia M. C.;Kuiper, Roland P.;Jansen, Joop H.
通讯作者：
Jansen, Joop H.
影响因子：
56.9
作者：
Gaudet, F;Hodgson, JG;Jaenisch, R
通讯作者：
Jaenisch, R
DOI：
10.1126/science.1170116
发表时间：
2009-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Tahiliani M;Koh KP;Shen Y;Pastor WA;Bandukwala H;Brudno Y;Agarwal S;Iyer LM;Liu DR;Aravind L;Rao A
通讯作者：
Rao A
影响因子：
158.5
作者：
Delhommeau, Francois;Dupont, Sabrina;Bernard, Olivier A.
通讯作者：
Bernard, Olivier A.
影响因子：
30.8
作者：
Broeske, Ann-Marie;Vockentanz, Lena;Rosenbauer, Frank
通讯作者：
Rosenbauer, Frank