Characterization of the 13q14 tumor suppressor locus in CLL: identification of ALT1, an alternative splice variant of the LEU2 gene.
Characterization of the 13q14 tumor suppressor locus in CLL: identification of ALT1, an alternative splice variant of the LEU2 gene.
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发表时间：
2001-09
期刊：
影响因子：
11.2
通讯作者：
F. Bullrich;H. Fujii;G. Calin;H. Mabuchi;M. Negrini;Y. Pekarsky;L. Rassenti;H. Alder;John Calvin Reed;M. Keating;T. Kipps;C. Croce
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作者：
F. Bullrich;H. Fujii;G. Calin;H. Mabuchi;M. Negrini;Y. Pekarsky;L. Rassenti;H. Alder;John Calvin Reed;M. Keating;T. Kipps;C. Croce
染色体13 q14缺失是慢性淋巴细胞白血病（CLL）中最常见的遗传异常。为了鉴定13 q14基因组缺失靶向的假定肿瘤抑制基因，我们对跨越CLL最小缺失区域的13 q14处的790 kb片段进行了完全测序和表征。通过数据库同源性搜索和外显子预测分析鉴定该区域的转录序列。在该序列的着丝粒末端的200 kb包含5个CpG岛，3个先前鉴定的基因LEU 5/RFP 2、LEU 2和LEU 1，7个由>10个EST组成的EST簇中的7个，以及大量预测的外显子。对小鼠EST数据库的同源性搜索，使我们能够确定一个高度保守的替代第一外显子的LEU 2基因，产生了一种新的转录本，ALT 1（GenBank登录号AF 380424），它起源于一个G+C区附近的D13 S272标记。两个新的3'外显子的LEU 2也被确定，并存在于LEU 2和ALT 1转录本。然而，我们还没有发现白血病病例中的任何突变，或该区域mRNA表达的改变，这可能直接涉及这些mRNA在CLL的病理学。所有报道的基因所在的序列的着丝粒末端含有两倍于预期量的ALU重复序列，而端粒末端富含LINE 1，并含有4个长度大于4 kb的LINE 1元件，包括2个全长LINE 1序列。该序列的这一特征可能有利于染色体重排的发生，并可能赋予该区域不稳定性，导致缺失，从而可能导致尚未鉴定的肿瘤抑制基因。
Chromosome 13q14 deletions constitute the most common genetic abnormality in chronic lymphocytic leukemia (CLL). To identify the putative tumor suppressor gene targeted by 13q14 genomic loss, we completely sequenced and characterized a segment of 790 kb at 13q14 spanning the minimal region of loss in CLL. Transcribed sequences in the region were identified through database homology searches and exon-prediction analysis. Two-hundred kb at the centromeric end of the sequence contain five CpG islands, three previously identified genes LEU5/RFP2, LEU2, and LEU1, seven of seven EST clusters composed of >10 ESTs, and a large number of predicted exons. Homology searches against the mouse EST database have allowed us to identify a highly conserved alternative first exon of the LEU2 gene, giving rise to a novel transcript, ALT1 (GenBank accession no. AF380424), which originates within a G+C region in the vicinity of the D13S272 marker. Two novel 3' exons of LEU2 were also identified and are present in both LEU2 and ALT1 transcripts. However, we have not identified any mutations in leukemia cases, or alterations in expression of mRNAs in the region, that might directly implicate these mRNAs in the pathology of CLL. The centromeric end of the sequence, where all reported genes are located, contains twice the expected amount of ALU repeats, whereas the telomeric end is LINE1 rich and contains four LINE1 elements longer than 4 kb, including two full-length LINE1 sequences. This feature of the sequence may favor the occurrence of chromosomal rearrangements and may confer instability to the region, resulting in deletions that may inactivate an as yet unidentified tumor suppressor.