Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma
Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma
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DOI：
10.1182/blood.v95.2.619
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发表时间：
2000-01-15
期刊：
影响因子：
20.3
通讯作者：
Inghirami, G
中科院分区：
文献类型：
--
作者：
Chiarle, R;Budel, LM;Inghirami, G
套细胞淋巴瘤（Mantle cell lymphoma，MCL）是一种侵袭性肿瘤，其特征是细胞周期蛋白D1（cyclin D1）表达失调，其发生机制尚不清楚。作者研究了110例MCL中p53、E2 F-1以及CDK抑制剂p27和p21的表达，将其表达与增殖活性（Ki-67）联系起来，为了进行比较，他们也类似地分析了低级别MCL（12例MALT，16例CLL/SLL）和高级别（19例DLCL）淋巴瘤中，p53在大细胞MCL中更常见在MCL和DLCL中，E2 F-1+细胞核的百分比高，与Ki-67的高表达相关。大多数MCL（112例中的91例）和DLCL（19例中的12例）显示p27缺失;然而，MALT和CLL/SLL为pn阳性。逆转录-聚合酶链反应和体外蛋白降解试验表明，MCL具有正常的p27 mRNA表达，但通过蛋白酶体途径增加p27蛋白降解活性。MCL p53和p27表达与临床数据的相关性显示，总生存率降低与p53过表达（P =.001）、p27缺失（P =.002）或两者兼而有之有关。p53阴性病例中p27缺失患者的临床结局较差（P =.002）。这些结果表明，MCL有一个独特的细胞周期蛋白的表达类似于高级别淋巴瘤。MCL中p27的缺失和p53的过度表达是识别高风险患者的预后标志物。MCL中低水平的p27是由增强的蛋白酶体介导的降解引起的，这一证明应该鼓励更多的临床试验。
Mantle cell lymphoma (MCL) is an aggressive neoplasm characterized by the deregulated expression of cyclin D1 by t(11;14), The molecular mechanisms responsible for MCL's clinical behavior remain unclear. The authors have investigated the expression of p53, E2F-1, and the CDK inhibitors p27 and p21 in 110 MCLs, relating their expression to proliferative activity (Ki-67), For comparison, they have similarly analyzed low-grade (12 MALT, 16 CLL/SLL) and high-grade (19 DLCL) lymphomas, p53 was detected more frequently in large-cell MCL (I-MCL; 5 of 7) than in classical MCL (s-MCL; 13 of 103) and DLCL (8 of 19), In MCL and DLCL, the percentage of E2F-1+ nuclei was high, correlating with high Ki-67 expression. Most MCLs (91 of 112) and DLCLs (12 of 19) showed a loss of p27; MALT and CLL/SLL, however, were pn positive. Reverse transcription-polymerase chain reaction and in vitro protein degradation assays demonstrated that MCLs have normal p27 mRNA expression but increased p27 protein degradation activity via the proteasome pathway. Correlation of MCL p53 and p27 expression with clinical data showed an association between reduced overall survival rates and the overexpression of p53 (P =.001), the loss of p27 (P =.002), or both. Loss of p27 identified patients with a worse clinical outcome among p53 negative cases (P =.002). These findings demonstrated that MCL has a distinct cell cycle protein expression similar to that of high-grade lymphoma. The loss of p27 and the overexpression of p53 in MCL are prognostic markers that identify patients at high risk. The demonstration that low levels of p27 in MCL result from enhanced proteasome-mediated degradation should encourage additional clinical trials.