Journal
HEMATOLOGY
Volume 10, Issue -, Pages 117-126Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/10245330512331390140
Keywords
multiple myeloma; prognosis; gene expression profiling; DNA amplification; chromosome 1q21; CKS1B; p27(Kip1); cell cycle regulation
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The molecular basis for aggressive transformation of multiple myeloma (MM) and other cancers is not completely understood. Global gene expression profiling on highly purified malignant plasma cells from 351 newly diagnosed patients with MM treated with autologous stem cell transplantation revealed a statistically significant over-representation of chromosome I genes in a group of 70 genes whose expression was linked to poor outcome. In particular, over-expression of CKS1B, which maps to an amplicon at 1q21 in myeloma and regulates SCFSkp2-mediated ubquitination and proteolysis of the cyclin dependent kinase inhibitor p27(Kip1) was significantly over-expressed in patients with poor survival. Interphase fluorescence in-situ hybridization revealed that CKS1B expression was strongly correlated with DNA copy number in a subset of 197 cases (P < 0.0001) with both measurements. Validated in 224 patients lacking expression analysis, CKS1B gene amplification conferred a poor prognosis (P < 0.0001) and was an independent predictor of outcome in multivariate analyses (P = 0.002). CKS1B mRNA and protein expression were correlated and both were inversely correlated with p27(Kip1) protein levels. RNA interference of CKS1B messenger RNA in myeloma cell lines led to reduced CKS1B mRNA and protein, an accumulation of p27(Kip1), and profound growth inhibition. Based on these data we conclude that over-expression of CKS1B, mainly due to gene amplification, imparts a poor prognosis in MM, possibly as a result of enhanced degradation of p27(Kip1)
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