Gustafsson B, Christenson B, Hjalmar V, Winiarski J
Department of Pediatrics, Huddinge University Hospital, Karolinska Institutet, Huddinge, Sweden.
Med Pediatr Oncol. 2000 Feb;34(2):117-24. doi: 10.1002/(sici)1096-911x(200002)34:2<117::aid-mpo9>3.0.co;2-8.
Previous studies have suggested that altered expression or dysfunction of the tumor suppressor gene p53 or the oncogene MDM2 could indicate disease progression in children with leukemia who would fail to achieve complete remission or who would relapse. While these studies mainly have described aberrations of MDM2 and p53 function at the DNA and mRNA-level, we have examined p53 and MDM2 expression at the protein level. Mutation of the p53 tumor suppressor gene may result in cellular accumulation of the p53 protein, due to prolonged half-life of the abnormal protein. The p53 protein can also be rendered nonfunctional by overexpression of proteins that bind to p53, such as MDM2. Both pathways have been proposed to disrupt cell cycle regulation in humans. Recent studies have shown that increased expressions of MDM2 as well as of p53 can be detected at the protein level in the absence of gene amplification.
Forty-three bone marrow samples were analyzed immunohistochemically for p53 and MDM2. Twenty-nine bone marrow samples were obtained in children with active, prognostically unfavorable leukemia and MDS. Fourteen bone marrow samples were from children with non-malignant hematological disorders.
p53 protein was expressed in 12 patients and MDM2 in 17 patients with leukemia. In the control group MDM2 expression was detected in one child, while p53 was not found in any of the samples.
Our findings of p53 or MDM2 positive cells in a majority of children with unfavorable prognostic features suggests that dysfunction of the p53-dependent cell growth control have a role in the development of high risk leukemias.
先前的研究表明，肿瘤抑制基因p53或癌基因MDM2的表达改变或功能异常可能预示着白血病患儿病情进展，这些患儿无法实现完全缓解或将会复发。虽然这些研究主要描述了MDM2和p53功能在DNA和mRNA水平的异常，但我们检测了p53和MDM2在蛋白质水平的表达。p53肿瘤抑制基因的突变可能导致p53蛋白在细胞内蓄积，这是由于异常蛋白的半衰期延长所致。p53蛋白也可能因与p53结合的蛋白（如MDM2）过度表达而失去功能。这两种途径均被认为会破坏人类细胞周期调控。最近的研究表明，在没有基因扩增的情况下，也可在蛋白质水平检测到MDM2和p53表达增加。
对43份骨髓样本进行p53和MDM2免疫组化分析。29份骨髓样本取自患有活动性、预后不良白血病和骨髓增生异常综合征的患儿。14份骨髓样本来自患有非恶性血液系统疾病的患儿。
12例白血病患者p53蛋白表达阳性，17例白血病患者MDM2蛋白表达阳性。在对照组中，1名儿童检测到MDM2表达，而在任何样本中均未发现p53表达。
我们在大多数具有不良预后特征的患儿中发现p53或MDM2阳性细胞，这表明p53依赖的细胞生长调控功能异常在高危白血病的发生中起作用。
