Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells.
Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells.
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DOI：
10.1038/ncomms15102
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发表时间：
2017-04-25
影响因子：
16.6
通讯作者：
Xu M
中科院分区：
文献类型：
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作者：
Pan F;Wingo TS;Zhao Z;Gao R;Makishima H;Qu G;Lin L;Yu M;Ortega JR;Wang J;Nazha A;Chen L;Yao B;Liu C;Chen S;Weeks O;Ni H;Phillips BL;Huang S;Wang J;He C;Li GM;Radivoyevitch T;Aifantis I;Maciejewski JP;Yang FC;Jin P;Xu M
TET2 is a dioxygenase that catalyses multiple steps of 5-methylcytosine oxidation. Although TET2 mutations frequently occur in various types of haematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. Here we show that Tet2−/− mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. Exome sequencing of Tet2−/− tumours reveals accumulation of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently deleted/mutated in human haematological malignancies. Single-cell-targeted sequencing of wild-type and premalignant Tet2−/− Lin−c-Kit+ cells shows higher mutation frequencies in Tet2−/− cells. We further show that the increased mutational burden is particularly high at genomic sites that gained 5-hydroxymethylcytosine, where TET2 normally binds. Furthermore, TET2-mutated myeloid malignancy patients have significantly more mutational events than patients with wild-type TET2. Thus, Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells, suggesting a novel TET2 loss-mediated mechanism of haematological malignancy pathogenesis. TET2 catalyses DNA demethylation and is mutated in various blood cancers; in particular Tet2 null mice develop haematological neoplasms. Here the authors show that this effect could be due to the increased frequency of mutation associated with TET2 loss in haematopoietic stem/progenitor cells.
