Frequent pathway mutations of splicing machinery in myelodysplasia
Frequent pathway mutations of splicing machinery in myelodysplasia
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DOI：
10.1038/nature10496
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发表时间：
2011-10-06
期刊：
影响因子：
64.8
通讯作者：
Ogawa, Seishi
中科院分区：
文献类型：
--
作者：
Yoshida, Kenichi;Sanada, Masashi;Ogawa, Seishi
骨髓增生异常综合征和相关疾病（骨髓增生异常）是一组异质性骨髓肿瘤，表现为血细胞生成失调，伴有骨髓增生异常的证据和急性骨髓性白血病的易感性，其发病机制尚不完全清楚。在这里，我们报告了29例骨髓增生异常标本的全外显子组测序，意外地发现了涉及RNA剪接机制多个组件的新途径突变，包括U2 AF 35，ZRSR 2，SRSF 2和SF 3B 1。在一项大型系列分析中，这些剪接途径突变在表现出骨髓增生异常特征的骨髓肿瘤中很常见（相似于45%至相似于85%），且具有高度特异性。显然，大多数突变以相互排斥的方式发生，影响前体mRNA加工过程中参与3 '-剪接位点识别的基因，诱导异常RNA剪接和造血功能受损。我们的研究结果提供了第一个证据表明，主要剪接成分的遗传改变可能涉及人类的发病机制，也暗示了一种新的治疗骨髓增生异常的可能性。
Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent (similar to 45 to similar to 85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3'-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved inhuman pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.