Overexpression of the MDM2 gene by childhood acute lymphoblastic leukemia cells expressing the wild-type p53 gene.
Overexpression of the MDM2 gene by childhood acute lymphoblastic leukemia cells expressing the wild-type p53 gene.
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DOI：
10.1182/blood.v85.6.1608.bloodjournal8561608
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发表时间：
1995-03
期刊：
影响因子：
20.3
通讯作者：
Mu-xiang Zhou;A. Yeager;Stephen;Smith;Harry;Findley
中科院分区：
文献类型：
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作者：
Mu-xiang Zhou;A. Yeager;Stephen;Smith;Harry;Findley
野生型（wt）p53肿瘤抑制基因通常在人类恶性肿瘤中失活，无论是通过突变还是通过表达缺失。另一个提出的wt-p53失活机制是鼠双微体2（MDM 2）基因的扩增和MDM 2蛋白的过表达，其结合p53并消除其肿瘤抑制功能。为了研究MDM 2在儿童急性淋巴细胞白血病（ALL）中wt-p53失活的潜在作用，我们在19个儿童ALL细胞系和1个儿童急性髓细胞白血病（AML）细胞系中检测了MDM 2和p53的表达，以及p53突变的发生和MDM 2基因的可能扩增。虽然我们没有发现任何白血病细胞系中MDM 2基因的显著扩增，但我们在所有10个表达wt-p53的细胞系中检测到MDM 2的过表达。在没有MDM 2基因过表达的10个细胞系中，6个细胞系（包括AML细胞系）不表达p53，4个细胞系表达外显子7和8中具有单点突变的突变型p53。为了确定原代白血病细胞是否表现出类似的相关性，我们分析了来自7名建立细胞系的患者的原始冷冻保存的白血病骨髓细胞。我们从原代白血病细胞和相应的细胞系中获得了类似的结果：MDM 2的过表达存在于表达wt-p53的原代细胞中，但不存在于缺乏wt-p53表达的细胞中。这些发现表明MDM 2在儿童ALL发病机制中的重要作用，其中白血病细胞表达wt-p53。
The wild-type (wt) p53 tumor suppressor gene is commonly inactivated in human malignancies, either by mutations or by loss of expression. An additional proposed mechanism for inactivation of wt-p53 is amplification of the murine double minute 2 (MDM2) gene and overexpression of the MDM2 protein, which binds to p53 and eliminates its tumor suppressor function. To investigate a potential role for MDM2 in the inactivation of wt-p53 in pediatric acute lymphoblastic leukemia (ALL), we examined the expression of MDM2 and p53, as well as the occurrence of p53 mutations and possible amplification of the MDM2 gene, in 19 pediatric ALL cell lines and one pediatric acute myelogenous leukemia (AML) line. Although we did not find significant amplification of the MDM2 gene in any of the leukemic lines, we detected overexpression of MDM2 in all 10 lines that expressed wt-p53. Of the 10 lines without overexpression of the MDM2 gene, six (including the AML line) did not express p53, and four expressed mutant p53 with single point mutations in exons 7 and 8. To determine whether primary leukemic cells showed a similar correlation, we analyzed the original cryopreserved leukemic bone marrow cells from seven patients from whom cell lines were established. We obtained similar results from both the primary leukemic cells and the corresponding cell lines: overexpression of MDM2 was present in primary cells that expressed wt-p53 but not in cells that lacked expression of wt-p53. These findings suggest an important role for MDM2 in the pathogenesis of pediatric ALL in which leukemic cells express wt-p53.