Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis
Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis
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DOI：
10.1182/blood-2011-12-399774
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发表时间：
2012-04-05
期刊：
影响因子：
20.3
通讯作者：
Maciejewski, Jaroslaw P.
中科院分区：
文献类型：
--
作者：
Makishima, Hideki;Visconte, Valeria;Maciejewski, Jaroslaw P.
骨髓增生异常综合征（MDS）是一种慢性且常常进行性的骨髓肿瘤，其组织形态学和临床病程具有显着的异质性。 MDS的发病机制涉及多种体细胞突变。最近，在一种独特形式的环状铁粒幼细胞 MDS 中发现了编码剪接体蛋白 SF3B1 的基因突变。对 15 名骨髓肿瘤患者进行了全外显子组测序，并鉴定了剪接体基因的体细胞突变。对 310 名患者进行桑格测序以评估表型/基因型关联。为了确定剪接体突变的功能效应，我们通过 RNA 深度测序评估了前 mRNA 剪接特征。我们在剪接体基因中发现了其他体细胞突变，包括 SF3B1、U2AF1 和 SRSF2。这些突变改变了 mRNA 前体的剪接模式。 SF3B1 突变常见于伴有环状铁粒幼细胞的低危 MDS，而 U2AF1 和 SRSF2 突变常见于慢性粒单核细胞白血病和晚期形式的 MDS。 SF3B1 突变与良好的预后相关，而 U2AF1 和 SRSF2 突变则预示着较短的生存期。影响剪接体基因的突变导致剪接缺陷，这是一种新的白血病发生途径。剪接体基因可能是肿瘤抑制基因，它们的突变可能构成诊断生物标志物，有可能作为治疗靶点。 (Blood. 2012; 119(14): 3203-3210)
Myelodysplastic syndromes (MDSs) are chronic and often progressive myeloid neoplasms associated with remarkable heterogeneity in the histomorphology and clinical course. Various somatic mutations are involved in the pathogenesis of MDS. Recently, mutations in a gene encoding a spliceosomal protein, SF3B1, were discovered in a distinct form of MDS with ring sideroblasts. Whole exome sequencing of 15 patients with myeloid neoplasms was performed, and somatic mutations in spliceosomal genes were identified. Sanger sequencing of 310 patients was performed to assess phenotype/genotype associations. To determine the functional effect of spliceosomal mutations, we evaluated pre-mRNA splicing profiles by RNA deep sequencing. We identified additional somatic mutations in spliceosomal genes, including SF3B1, U2AF1, and SRSF2. These mutations alter pre-mRNA splicing patterns. SF3B1 mutations are prevalent in low-risk MDS with ring sideroblasts, whereas U2AF1 and SRSF2 mutations are frequent in chronic myelomonocytic leukemia and advanced forms of MDS. SF3B1 mutations are associated with a favorable prognosis, whereas U2AF1 and SRSF2 mutations are predictive for shorter survival. Mutations affecting spliceosomal genes that result in defective splicing are a new leukemogenic pathway. Spliceosomal genes are probably tumor suppressors, and their mutations may constitute diagnostic biomarkers that could potentially serve as therapeutic targets. (Blood. 2012; 119(14): 3203-3210)