Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia
Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia
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DOI：
10.1038/ng.788
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发表时间：
2011-04-01
期刊：
影响因子：
30.8
通讯作者：
Chen, Sai-Juan
中科院分区：
文献类型：
--
作者：
Yan, Xiao-Jing;Xu, Jie;Chen, Sai-Juan
异常的表观遗传调控与肿瘤的发生有关。我们在此报告通过外显子组测序鉴定急性单核细胞白血病，急性髓性白血病（AML-M5）的M5亚型的体细胞突变。我们在112例病例中发现23例（20.5%）的DNMT3A（编码DNA甲基转移酶3A）突变。DNMT3A突变体在体外表现出酶活性降低或对组蛋白H3的异常亲和力。值得注意的是，与没有这种变化的样本相比，DNMT3A突变样本中的DNA甲基化模式和/或基因表达谱（如HOXB基因）发生了变化。伴有DNMT3A突变的白血病是AML-M5个体中预后较差的一组，发病年龄较大，且以单核细胞为主。对其他白血病亚型的筛查显示，13.6%的急性髓细胞白血病（AML-M4）病例中Arg882发生改变。我们的工作提示了异常DNA甲基转移酶活性在急性单核细胞白血病发病机制中的作用，并为相关病例提供了一个有用的新生物标志物。
Abnormal epigenetic regulation has been implicated in oncogenesis. We report here the identification of somatic mutations by exome sequencing in acute monocytic leukemia, the M5 subtype of acute myeloid leukemia (AML-M5). We discovered mutations in DNMT3A (encoding DNA methyltransferase 3A) in 23 of 112 (20.5%) cases. The DNMT3A mutants showed reduced enzymatic activity or aberrant affinity to histone H3 in vitro. Notably, there were alterations of DNA methylation patterns and/or gene expression profiles (such as HOXB genes) in samples with DNMT3A mutations as compared with those without such changes. Leukemias with DNMT3A mutations constituted a group of poor prognosis with elderly disease onset and of promonocytic as well as monocytic predominance among AML-M5 individuals. Screening other leukemia subtypes showed Arg882 alterations in 13.6% of acute myelomonocytic leukemia (AML-M4) cases. Our work suggests a contribution of aberrant DNA methyltransferase activity to the pathogenesis of acute monocytic leukemia and provides a useful new biomarker for relevant cases.