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Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma.
- Source :
-
Blood [Blood] 2000 Jan 15; Vol. 95 (2), pp. 619-26. - Publication Year :
- 2000
-
Abstract
- 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 (l-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 p27 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. (Blood. 2000;95:619-626) (Blood. 2000;95:619-626)
- Subjects :
- B-Lymphocytes metabolism
Biomarkers, Tumor analysis
Biomarkers, Tumor genetics
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Cyclins genetics
E2F Transcription Factors
E2F1 Transcription Factor
Humans
Ki-67 Antigen analysis
Lymphoid Tissue metabolism
Lymphoma genetics
Lymphoma pathology
Lymphoma, B-Cell, Marginal Zone genetics
Lymphoma, B-Cell, Marginal Zone mortality
Lymphoma, B-Cell, Marginal Zone pathology
Lymphoma, Mantle-Cell mortality
Lymphoma, Mantle-Cell pathology
Lymphoma, Mantle-Cell surgery
Proteasome Endopeptidase Complex
Retinoblastoma-Binding Protein 1
Survival Rate
Transcription Factor DP1
Transcription Factors genetics
Tumor Suppressor Protein p53 genetics
Carrier Proteins
Cell Cycle Proteins
Cyclin-Dependent Kinases antagonists & inhibitors
Cysteine Endopeptidases metabolism
DNA-Binding Proteins
Lymphoma, Mantle-Cell genetics
Microtubule-Associated Proteins genetics
Microtubule-Associated Proteins metabolism
Multienzyme Complexes metabolism
Tumor Suppressor Proteins
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 95
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 10627471