Alterations of the p53, p21, p16, p15 and RAS genes in childhood T-cell acute lymphoblastic leukemia
Alterations of the p53, p21, p16, p15 and RAS genes in childhood T-cell acute lymphoblastic leukemia
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DOI：
10.1016/s0145-2126(98)00146-5
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发表时间：
1999-02-01
影响因子：
2.7
通讯作者：
Hayashi, Y
中科院分区：
文献类型：
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作者：
Kawamura, M;Ohnishi, H;Hayashi, Y
采用聚合酶链反应-单链构象多态性（PCR-SSCP）分析和直接测序法，研究了儿童T细胞急性淋巴细胞白血病（T-ALL）及其细胞系中p53、p21、p16、p15和RAS基因的改变。p53基因突变在诊断时的57例患者中有3例（5%），复发时的14例患者中有1例（7%），在18个细胞系中有12例（67%）。在这12个细胞系中，有4个细胞系具有两个以上的p53基因突变。在同时检测原始新鲜白血病细胞的5个细胞系中，有4个发现了p53突变。然而，四个新鲜的白血病细胞中只有一个具有相同的突变。所有p53突变患者在病程中均死亡。在71个新鲜样本和18个细胞系中未发现p21基因突变。在57例新诊断的T-ALL患者中有2例（4%）发现N-RAS突变，在18个细胞系中有4个（22%）发现N-RAS突变，而在复发时的任何样本中均未检测到突变。p16基因的改变被发现在18的47（38%）患者在诊断和7的14（50%）在复发。这些差异不具有统计学显著性。无事件患者和其余患者之间p16和p15基因改变的频率没有差异。此外，我们发现在7例无纯合性缺失的患者中，有3例存在p16基因甲基化，这表明在T-ALL中p16失活的频率高于以往的报道。有趣的是，我们发现一个等位基因被甲基化失活，另一个等位基因在一个细胞系（KOPT-K1）中发生无义突变，导致p16蛋白表达丧失。这种类型的p16失活迄今尚未报道白血病。结论：（1）p53突变在T-ALL的诊断中并不常见，但往往与不良的临床结局相关;（2）RAS和p21突变可能不参与T-ALL的发病机制;（3）T-ALL的发生不仅与p16、p15基因的频繁改变有关，而且与p16基因甲基化有关，和（4）这5个基因独立参与T-ALL。(C)1999 Elsevier Science Ltd.保留所有权利。
We investigated the alterations of the p53, p21, p16, p15 and RAS genes in childhood T-cell acute lymphoblastic leukemia (T-ALL) and T-ALL cell lines by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing. Mutations of the p53 gene were found in three of 57 (5%) patients at diagnosis, one of 14 (7%) patients at relapse and in 12 of 18 (67%) cell lines. In these 12 cell lines, four had more than two mutations of the p53 gene. The p53 mutations were found in four of five cell lines whose original fresh leukemic cells were simultaneously examined original fresh leukemic cells. However, only one of the four fresh leukemic cells had the same mutation. All patients with p53 mutations in the course of disease died. Mutations of the p21 gene were not identified in 71 fresh samples and in 18 cell lines. N-RAS mutations were found in two of 57 (4%) fresh T-ALL patients at diagnosis, and four of 18 cell lines (22%), whereas no mutations were detected in any samples at relapse. Alterations of the p16 gene were found in 18 of 47 (38%) patients at diagnosis and in seven of 14 (50%) at relapse. These differences were not statistically significant. There were no differences in the frequency of alteration of the p16 and p15 genes between event-free patients and the remaining patients. Furthermore, we found the methylation of p16 gene in three of seven patients lacking homozygous deletions, suggesting higher frequency of p16 inactivation than previous reports in T-ALL. Interestingly, we found that one allele is inactivated by methylation and another allele had nonsense mutation in one cell line (KOPT-K1), resulting in loss of protein expression of p16. This type of p16 inactivation has not been so far reported in leukemia. We conclude that, (1) p53 mutations are infrequent at diagnosis but tend to be associated with poor clinical outcome; (2) RAS and p21 mutations may not be involved in the pathogenesis of T-ALL; (3) not only frequent alterations of p16 and p15 genes but also methylation of p16 gene are involved in initiating the leukemogenesis of T-ALLs, and (4) these 5 genes are independently involved in T-ALL. (C) 1999 Elsevier Science Ltd. All rights reserved.