Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive neoplasm characterized by the d eregulated expression of cyclin D1 by t(11;14), The molecular mechanisms re sponsible for MCL's clinical behavior remain unclear. The authors have inve stigated the expression of p53, E2F-1, and the CDK inhibitors p27 and p21 i n 110 MCLs, relating their expression to proliferative activity (Ki-67), Fo r comparison, they have similarly analyzed low-grade (12 MALT, 16 CLL/SLL) and high-grade (19 DLCL) lymphomas, p53 was detected more frequently in lar ge-cell MCL (I-MCL; 5 of 7) than in classical MCL (s-MCL; 13 of 103) and DL CL (8 of 19), In MCL and DLCL, the percentage of E2F-1+ nuclei was high, co rrelating with high Ki-67 expression. Most MCLs (91 of 112) and DLCLs (12 o f 19) showed a loss of p27; MALT and CLL/SLL, however, were pn positive. Re verse transcription-polymerase chain reaction and in vitro protein degradat ion assays demonstrated that MCLs have normal p27 mRNA expression but incre ased p27 protein degradation activity via the proteasome pathway. Correlati on of MCL p53 and p27 expression with clinical data showed an association b etween reduced overall survival rates and the overexpression of p53 (P =.00 1), the loss of p27 (P =.002), or both. Loss of p27 identified patients wit h a worse clinical outcome among p53 negative cases (P =.002). These findin gs demonstrated that MCL has a distinct cell cycle protein expression simil ar to that of high-grade lymphoma. The loss of p27 and the overexpression o f p53 in MCL are prognostic markers that identify patients at high risk. Th e demonstration that low levels of p27 in MCL result from enhanced proteaso me-mediated degradation should encourage additional clinical trials.