Inactivation of RB1 in mantle-cell lymphoma detected by nonsense-mediated mRNA decay pathway inhibition and microarray analysis
Inactivation of RB1 in mantle-cell lymphoma detected by nonsense-mediated mRNA decay pathway inhibition and microarray analysis
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DOI：
10.1182/blood-2006-11-057208
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发表时间：
2007-06-15
期刊：
影响因子：
20.3
通讯作者：
Jares, Pedro
中科院分区：
文献类型：
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作者：
Pinyol, Magda;Bea, Silvia;Jares, Pedro
套细胞淋巴瘤（MCL）的遗传特征是易位t（11;14）（q13;q32）和大量的继发性染色体异常。为了确定这种淋巴瘤中失活的基因，我们检查了5个MCL细胞系，遵循先前在具有微卫星不稳定性的肿瘤中描述的策略，该策略基于无义介导的mRNA衰变途径和基因表达谱的联合抑制。这种方法，连同保守算法的设计，用于分析的结果，允许识别3个基因携带提前终止密码子。这些基因是具有先前在JEKO-1中描述的突变的p53，REC-1中的白细胞衍生的精氨酸氨基肽酶（LRAP）基因，其显示新的剪接同种型，产生提前终止密码子，以及UPN-1中的RB 1，其含有基因内纯合缺失，导致截短的转录物和蛋白质表达的完全丧失。在2例原发性MCL中也检测到新的LRAP亚型，而在UPN-1来源的原发性肿瘤和1例额外的胚样MCL中发现了RB 1的失活基因内缺失。这些肿瘤携带p53的伴随失活，而p16 INK 4a是野生型。这些结果首次表明，RB 1可能是失活的侵略性MCL基因内缺失。
Mantle-cell lymphoma (MCL) is genetically characterized by the translocation t(11;14)(q13;q32) and a high number of secondary chromosomal abnormalities. To identify genes inactivated in this lymphoma, we examined 5 MCL cell lines following a strategy previously described in tumors with microsatellite instability that is based on the combined inhibition of the nonsense-mediated mRNA decay pathway and gene-expression profiling. This approach, together with the design of a conservative algorithm for analysis of the results, allowed the identification of 3 genes carrying premature stop codons. These genes were p53 with a mutation previously described in JEKO-1, the leukocyte-derived arginine aminopeptidase (LRAP) gene in REC-1 that showed a new splicing isoform generating a premature stop codon, and RB1 in UPN-1 that contained an intragenic homozygous deletion resulting in a truncated transcript and total loss of protein expression. The new LRAP isoform was detected also in 2 primary MCLs, whereas inactivating intragenic deletions of RB1 were found in the primary tumor from which UPN-1 was derived and 1 additional blastoid MCL. These tumors carried a concomitant inactivation of p53, whereas p16INK4a was wild type. These results indicate for the first time that RB1 may be inactivated in aggressive MCL by intragenic deletions.