Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma.

Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Hematology (Impact Factor: 1.19). 09/2005; 10 Suppl 1:117-26. DOI: 10.1080/10245330512331390140
Source: PubMed

ABSTRACT 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 1 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 SCF(Skp2)-mediated ubquitination and proteolysis of the cyclin dependent kinase inhibitor p27Kip1 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 p27Kip1, 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 p27Kip1.

1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cytogenetic abnormalities have emerged as the major novel prognostic factors in multiple myeloma (MM) patients. This meta-analysis comprehensively investigates the association between the cytogenetic abnormalities and survival of MM patients. We searched the PubMed, EMBASE, SCOPUS, and Cochrane databases for articles published until February, 2014. Thirty eligible studies involving 10276 patients were included to examine the association of three chromosomal abnormalities, t (4; 14), del (17p), and Amp (1q21), with survival in MM patients. The main outcome measures were progression-free survival (PFS) and overall survival (OS). Individuals with t (4; 14), del (17p), and Amp (1q21) had low OS and PFS. In a subgroup analysis for therapy regimen, lenalidomide- and bortezomib-based therapies increased the PFS of patients with Amp (1q21) (HR=1.50, 95% CI=0.95-2.36, p=0.084) and t (4; 14) (HR=1.38, 95% CI=0.90-2.11, p=0.143). The presence of del (17p) elicited no significant influence on the prognosis of patients under different therapy regimens. Our meta-analysis provides globally quantifiable confirmation of the adverse prognostic value of t (4; 14), del (17p), and Amp (1q21) in OS and PFS for MM patients. Lenalidomide- and bortezomib-based therapies were partly conducive to improve the prognosis of individuals with t (4; 14). Bortezomib-based therapy can partly improve the PFS of patients with Amp (1q21).
    International Journal of Clinical and Experimental Medicine 01/2014; 7(11):4051-62. · 1.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Molecular studies have shown that multiple myeloma is a highly genetically heterogonous disease which may manifest itself as any number of diverse subtypes each with variable clinicopathological features and outcomes. Given this genetic heterogeneity, a universal approach to treatment of myeloma is unlikely to be successful for all patients and instead we should strive for the goal of personalised therapy using rationally informed targeted strategies. Current DNA sequencing technologies allow for whole genome and exome analysis of patient myeloma samples that yield vast amounts of genetic data and provide a mutational overview of the disease. However, the clinical utility of this information currently lags far behind the sequencing technology which is increasingly being incorporated into clinical practice. This paper attempts to address this shortcoming by proposing a novel genetically based "traffic-light" risk stratification system for myeloma, termed the RAG (Red, Amber, Green) model, which represents a simplified concept of how complex genetic data may be compressed into an aggregate risk score. The model aims to incorporate all known clinically important trisomies, translocations, and mutations in myeloma and utilise these to produce a score between 1.0 and 3.0 that can be incorporated into diagnostic, prognostic, and treatment algorithms for the patient.
    Bone marrow research. 01/2014; 2014:526568.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Characteristic recurrent copy number aberrations (CNAs) play a key role in multiple myeloma (MM) pathogenesis and have important prognostic significance for MM patients. Array-based comparative genomic hybridization (aCGH) provides a powerful tool for genome-wide classification of CNAs and thus should be implemented into MM routine diagnostics. We demonstrate the possibility of effective utilization of oligonucleotide-based aCGH in 91 MM patients. Chromosomal aberrations associated with effect on the prognosis of MM were initially evaluated by I-FISH and were found in 93.4% (85/91). Incidence of hyperdiploidy was 49.5% (45/91); del(13)(q14) was detected in 57.1% (52/91); gain(1)(q21) occurred in 58.2% (53/91); del(17)(p13) was observed in 15.4% (14/91); and t(4;14)(p16;q32) was found in 18.6% (16/86). Genome-wide screening using Agilent 44K aCGH microarrays revealed copy number alterations in 100% (91/91). Most common deletions were found at 13q (58.9%), 1p (39.6%), and 8p (31.1%), whereas gain of whole 1q was the most often duplicated region (50.6%). Furthermore, frequent homozygous deletions of genes playing important role in myeloma biology such as TRAF3, BIRC1/BIRC2, RB1, or CDKN2C were observed. Taken together, we demonstrated the utilization of aCGH technique in clinical diagnostics as powerful tool for identification of unbalanced genomic abnormalities with prognostic significance for MM patients.
    BioMed Research International 01/2014; 2014:209670. · 2.71 Impact Factor


Available from