High incidence of potential p53 inactivation in poor outcome childhood acute lymphoblastic leukemia at diagnosis
High incidence of potential p53 inactivation in poor outcome childhood acute lymphoblastic leukemia at diagnosis
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DOI：
10.1182/blood.v87.3.1155.bloodjournal8731155
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发表时间：
1996-02-01
期刊：
影响因子：
20.3
通讯作者：
Haines, DS
中科院分区：
文献类型：
--
作者：
Marks, DI;Kurz, BW;Haines, DS
先前的研究表明，p53 基因突变在儿童急性淋巴细胞白血病 (ALL) 中并不常见。在 330 名患者的一系列研究中，发现 p53 突变的比例不到 3%。我们分析了 10 名诊断时患有 ALL 的儿童的骨髓单核细胞，这些儿童随后未能实现完全缓解，或者在获得完全缓解后 6 个月内出现 p53 基因突变和 mdm-2 过表达复发。我们发现三个孩子有 p53 基因突变，四个孩子过度表达 mdm-2。此外，比较这些患者中 mdm-2 RNA 和蛋白质相对水平的实验表明，mdm-2 过度表达可能发生在原代白血病细胞的转录和转录后水平。尽管我们无法将儿童 ALL 中的 Waf-1 RNA 表达与 p53 状态联系起来，但我们的数据显示，在这些患者中，很大一部分患者可能通过多种机制使 p53 失活，并证明这些改变可以在诊断时检测到。因此，p53 通路的失活对于对治疗没有反应的 ALL 儿童可能很重要，并且可能有助于早期识别需要替代疗法的儿童。 (C) 1996 年，美国血液学会。
Previous studies have indicated that p53 gene mutations were an uncommon event in acute lymphoblastic leukemia (ALL) in children. In one series of 330 patients, p53 mutations were seen in fewer than 3%. We analyzed bone marrow mononuclear cells derived from 10 children with ALL at diagnosis who subsequently failed to achieve a complete remission or who developed relapse within 6 months of attaining complete remission for p53 gene mutations and mdm-2 overexpression. We found that three children had p53 gene mutations, and four overexpressed mdm-2. Also, experiments comparing relative levels of mdm-2 RNA and protein in these patients demonstrated that mdm-2 overexpression can occur at the transcriptional and posttranscriptional level in primary leukemic cells. Although we were unable to link Waf-1 RNA expression with p53 status in childhood ALL, our data show potential p53 inactivation by multiple mechanisms in a large percentage of these patients and demonstrate that these alterations can be detected at diagnosis. Inactivation of the p53 pathway may, therefore, be important in children with ALL who fail to respond to treatment and may be useful for the early identification of children requiring alternative therapies. (C) 1996 by The American Society of Hematology.