Mutational and expression analysis of the chromosome 12p candidate tumor suppressor genes in pre-B acute lymphoblastic leukemia
Mutational and expression analysis of the chromosome 12p candidate tumor suppressor genes in pre-B acute lymphoblastic leukemia
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DOI：
10.1038/sj.leu.2403441
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发表时间：
2004-09-01
期刊：
影响因子：
11.4
通讯作者：
Sinnett, D
中科院分区：
文献类型：
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作者：
Montpetit, A;Larose, J;Sinnett, D
染色体 12p12-13 上的等位基因丢失与儿童急性淋巴细胞白血病 (ALL) 和多种实体瘤相关，表明存在抑癌基因座。最近构建的该基因座的转录图谱使得能够鉴定八个基因，其中五个是以前已知的：ETV6、BCL-G、LRP6、MKP-7 和 CDKN1B。其他三个候选基因 LOH12CR1、LOH12CR2 和 LOH12CR3 没有已知的功能。为了评估一个（或多个）候选基因是否是 12p12-13 缺失的实际目标，我们检查了 ALL 患者中这些基因的基因组学和表达状态。尽管我们在这些基因中发现了 9 个 DNA 变异，但在 12p 半合子缺失患者的白血病细胞中没有发现失活突变。表达分析显示，大多数 12p 半合子缺失样本还携带 t(12;21) 易位，其中没有一个从非易位等位基因表达 ETV6。此外，我们观察到一例没有删除ETV6的t(12;21)，其中该基因的表达大大降低，表明不同的失活机制。其他基因均未表现出表达显着下降，表明 ETV6 确实是 ALL 患者中缺失的目标。
Allelic losses on chromosome 12p12-13 are associated with childhood acute lymphoblastic leukemia ( ALL) and several solid neoplasias, suggesting the presence of a tumor suppressor locus. The recent construction of a transcription map of this locus has enabled the identification of eight genes, of which five were previously known: ETV6, BCL-G, LRP6, MKP-7, and CDKN1B. The three other candidate genes, LOH12CR1, LOH12CR2, and LOH12CR3, have no known functions. To evaluate whether one ( or more) of the candidate genes is the actual target of the 12p12-13 deletions, we examined the genomics and the expression status of these genes in ALL patients. Although we found nine DNA variants in these genes, no inactivating mutations were found in the leukemia cells of patients with 12p hemizygous deletions. Expression analysis revealed that most 12p hemizygously deleted samples also carried a t(12; 21) translocation, of which none expressed ETV6 from the nontranslocated allele. Furthermore, we observed one case of t( 12; 21) without deletion of ETV6, in which the expression of this gene was greatly reduced, indicating a different mechanism of inactivation. None of the other genes showed a significant decrease in expression, suggesting that ETV6 is indeed the target of deletions in ALL patients.