Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival
Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival
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DOI：
10.1182/blood-2006-08-039859
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发表时间：
2007-06-01
期刊：
影响因子：
20.3
通讯作者：
Staudt, Louis M.
中科院分区：
文献类型：
--
作者：
Wiestner, Adrian;Tehrani, Mahsa;Staudt, Louis M.
套细胞淋巴瘤（MCL）肿瘤增殖率的基因表达特征是诊断后生存时间的首要分子预测因子。许多强增殖性MCL肿瘤具有异常高的细胞周期蛋白D1 mRNA水平，并优先表达短的细胞周期蛋白D1 mRNA亚型。我们在这里证明，这些短的mRNA是细胞周期蛋白D1 a亚型与截短的UTR，而不是选择性剪接的细胞周期蛋白D1 b mRNA亚型。在15个具有截短的cyclin D1 mRNA的MCL肿瘤中，7个在CCND 1 3 'UTR区域具有基因组缺失。在另外3个中，CCND 1含有点突变，产生了过早的多聚腺苷酸化信号，产生了缺乏大部分3 'UTR的1.5-kb mRNA。这两种类型的基因组改变创建转录缺乏mRNA不稳定元素存在于野生型细胞周期蛋白D1 a mRNA。在Z-138 MCL细胞系中也存在由于3 'UTR突变引起的过早多聚腺苷酸化，该细胞系同时表达截短的和全长的细胞周期蛋白D1 a mRNA。在这些细胞中，短的cyclin D1 a mRNA的半衰期比全长mRNA的半衰期长得多。我们的结论是CCND 1 3 'UTR结构的改变可以显着增加其致癌作用，并恶化MCL患者的临床过程。
A gene expression signature of tumor proliferation rate in mantle cell lymphoma (MCL) is an overriding molecular predictor of the length of survival following diagnosis. Many strongly proliferative MCL tumors have exceptionally high cyclin D1 mRNA levels and preferentially express short cyclin D1 mRNA isoforms. We demonstrate here that these short mRNAs are cyclin D1a isoforms with truncated UTRs, not alternatively spliced cyclin D1b mRNA isoforms. Among 15 MCL tumors with truncated cyclin D1 mRNAs, 7 had genomic deletions in the CCND1 3'UTR region. In 3 others, CCND1 contained point mutations that created premature polyadenylation signals, giving rise to 1.5-kb mRNAs lacking most of the 3'UTR. Both types of genomic alteration created transcripts lacking mRNA destabilization elements present in the wild-type cyclin D1a mRNA. Premature polyadenylation due to a 3'UTR mutation also was present in the Z-138 MCL cell line, which expressed both truncated and full-length cyclin D1a mRNAs. In these cells, the half-life of the short cyclin D1a mRNA was much longer than that of the full-length mRNA. We conclude that alterations of CCND1 3'UTR structure can significantly increase its oncogenic effect and worsen the clinical course of MCL patients.