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Nature:骨癌中发生突变的TET

来源:Nature 中文 2010-12-09 09:08

TET家族的酶在DNA中将5-甲基胞嘧啶转化为5-羟甲基胞嘧啶(5-hmC)。编码TET2的基因中的突变在恶性骨髓瘤中普遍存在。现在,这些与疾病有关的突变被发现降低TET2的催化活性:来自TET2突变患者的骨髓样品在基因组DNA中的5-hmC水平较低,而且TET2是正常造血分化所必需的。对基因组中5-hmC水平的测定也许会被证明是骨癌的一个有价值的诊断工具。(生物谷Bioon.com)

生物谷推荐原文出处:

Nature  doi:10.1038/nature09586

Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2

Myunggon Ko,Yun Huang,Anna M. Jankowska,Utz J. Pape,Mamta Tahiliani,Hozefa S. Bandukwala,Jungeun An,Edward D. Lamperti,Kian Peng Koh,Rebecca Ganetzky,X. Shirley Liu,L. Aravind,Suneet Agarwal,Jaroslaw P. Maciejewski& Anjana Rao

TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA1, 2. 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 malignancies3. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML)4, 5, 6, 7, 8, 9, 10, 11, 12. We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC 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 5hmC versus healthy controls, but samples from patients with low 5hmC 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 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs.

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