Splicing factor gene mutations in hematologic malignancies.
Splicing factor gene mutations in hematologic malignancies.
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DOI：
10.1182/blood-2016-10-692400
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发表时间：
2017-03
期刊：
影响因子：
20.3
通讯作者：
B. Saez;M. Walter;T. Graubert
中科院分区：
文献类型：
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作者：
B. Saez;M. Walter;T. Graubert
选择性剪接从单个mRNA前体产生多种信使RNA（mRNA）转录物，并有助于我们蛋白质组的复杂性。剪接在癌症中受到多种机制的干扰。剪接因子的复发性突变已成为几种血液恶性肿瘤的标志。剪接因子突变往往发生在骨髓癌的创始克隆中，并且这些突变最近已在来自具有克隆造血的正常健康老年个体的血细胞中被鉴定，这些个体随后发展成造血恶性肿瘤的风险增加，这表明这些突变有助于疾病的发生。剪接因子突变改变原代患者和小鼠造血细胞中的剪接模式，并改变动物模型中的造血分化和成熟。在这一领域的最新进展进行了审查，强调剪接因子突变的临床后果，从动物模型的机制的见解，并针对前体mRNA剪接途径的新疗法的发展的影响。
Alternative splicing generates a diversity of messenger RNA (mRNA) transcripts from a single mRNA precursor and contributes to the complexity of our proteome. Splicing is perturbed by a variety of mechanisms in cancer. Recurrent mutations in splicing factors have emerged as a hallmark of several hematologic malignancies. Splicing factor mutations tend to occur in the founding clone of myeloid cancers, and these mutations have recently been identified in blood cells from normal, healthy elderly individuals with clonal hematopoiesis who are at increased risk of subsequently developing a hematopoietic malignancy, suggesting that these mutations contribute to disease initiation. Splicing factor mutations change the pattern of splicing in primary patient and mouse hematopoietic cells and alter hematopoietic differentiation and maturation in animal models. Recent developments in this field are reviewed here, with an emphasis on the clinical consequences of splicing factor mutations, mechanistic insights from animal models, and implications for development of novel therapies targeting the precursor mRNA splicing pathway.