Nature：骨癌中發生突變的TET

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　　導讀：TET家族的酶在DNA中將5-甲基胞嘧啶轉化為5-羥甲基胞嘧啶(5-hmC)。編碼TET2的基因中的突變在惡性骨髓瘤中普遍存在。現在，這些與疾病有關的突變被發現降低TET2的催化活性：來自TET2突變患者的骨髓樣品在基因組DNA中的5-hmC水平較低，而且TET2是正常造血分化所必需的。對基因組中5-hmC水平的測定也許會被證明是骨癌的一個有價值的診斷工具。

　　推薦原文出處：

　　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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　　腫瘤科藥師溫馨提醒：如果發生了骨癌，患者一般會發生病理性骨折或變形，很多骨癌都是由于骨折發展而來的，需要引起重視。

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