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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Routine cytogenetic and molecular genetic analysis of plasma cell malignancies, such as multiple myeloma, became widespread only recently. As the result of these investigations, it became clear that tumor cell karyotype is fundamental from the viewpoint of therapy selection and prognosis. It is worthwhile to distinguish hyperdiploid and nonhyperdiploid myeloma, while five separate prognostic groups (TCI-5) may be identified on the basis of immunoglobulin gene translocations and cyclin expression. Deletion of the q arm of chromosome 13 or amplification of region 1q21 (and the CKS1B gene) can identify further subgroups of poor prognosis and few therapeutic options. Meanwhile, tumors harboring translocation t(11;14) respond favorably to conventional chemotherapy and exhibit exceptionally good and long-lasting response to high-dose chemotherapy. Progression of the disease may coincide with complex translocations of the c-myc gene or deletions involving the p53 tumor-suppressor gene, spreading of ras-mutations. These events represent clonal evolution at great tumor cell mass and advanced disease, therefore, are only of secondary prognostic significance.
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PMID:[Molecular genetic methods for the prognostic criteria in multiple myeloma]. 1614 45

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.
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PMID:Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma. 1618 52

Multiple myeloma is a malignancy of antibody-secreting plasma cells that expand in the bone marrow. Although high-dose therapy/autologous stem cell transplantation has become the standard of care for patients with multiple myeloma, survival is highly variable and can range from a few years to >10 years after diagnosis. Application of high-throughput genomics on a large uniformly untreated cohort of patients has revealed that activation of 1 of the 3 cyclin D genes is a universal initiating event in this disease and that acquisition of abnormalities of chromosome 1 leads to activation of CKS1B, a regulator of p27Kip1 degradation. Synergy between cyclin D2 and CKS1B, but not cyclin D1 and CKS1B, may lead to early treatment failure.
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PMID:Using genomics to identify high-risk myeloma after autologous stem cell transplantation. 1639 89

The genetic events that lead to tumour progression in plasma cell dyscrasia are not well understood. Interphase cytoplasmic fluorescence in situ hybridisation was used to investigate the CKS1B amplification status (at 1q21) in clonal plasma cells from 123 patients: 23 monoclonal gammopathy of undetermined significance (MGUS), 75 multiple myeloma (MM) and 26 plasma cell leukaemia (PCL). While CKS1B amplification was absent in MGUS patients, such amplification (3-8 copies) was detected in 36% of newly diagnosed MM, 52% relapsed MM and 62% PCL (P < 0.001). Our results suggest that CKS1B amplification is associated with transformation from MGUS to MM and progression to PCL.
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PMID:Significant increase of CKS1B amplification from monoclonal gammopathy of undetermined significance to multiple myeloma and plasma cell leukaemia as demonstrated by interphase fluorescence in situ hybridisation. 1688 15

The prevalence and prognostic relevance of recurrent gains of CKS1B (cyclin kinase subunit 1B) gene at chromosome 1q21 region was investigated by interphase fluorescence in situ hybridisation in a cohort of 99 multiple myeloma (MM) patients treated with intensive chemotherapy followed by autologous stem cell transplantation. CKS1B amplification (3-8 CKS1B signals) was detected in 31of 99 (31%) patients and was associated with deletions of p53 (P = 0.003) and 13q (P = 0.039) but not with translocation t(11;14) or t(4;14). CKS1B amplification was associated with bone marrow plasmacytosis (P = 0.02), but there was no correlation with patient age, gender, disease stage, lytic bone lesions, albumin, creatinine, C-reactive protein or beta-2 microglobulin levels. Patients with CKS1B amplification had a significantly shorter progression-free survival than those without such amplification (18.5 vs. 25.7 months, P = 0.035). Likewise, a shorter overall survival (44.8 months vs. not reached) was observed; however, the difference did not reach statistical significance (P = 0.20). Seven patients had paired bone marrows obtained at diagnosis and at relapse, the percentage of cells with CKS1B amplification and the level of amplification were significantly increased in the relapse marrows. In this cohort of patients, CKS1B was frequently amplified in MM and may represent genetic instability associated with disease progression.
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PMID:Multiple myeloma patients with CKS1B gene amplification have a shorter progression-free survival post-autologous stem cell transplantation. 1699 83

Myeloma patients with unfavorable molecular cytogenetics have a poor prognosis irrespective of treatment with conventional chemotherapy or autologous stem cell transplant. To investigate whether bortezomib, a new proteasome inhibitor, is active in relapsed/refractory myeloma patients with genetic risk factors, we evaluated the outcome of 65 patients and correlated the clinical response with 13q deletion, translocations t(11;14) and t(4;14) and CKS1B amplification as detected by interphase cytoplasmic fluorescence in situ hybridization (cIg-FISH). Thirty-seven of 61 (61%) evaluable patients had an objective response to bortezomib with median progression free (PFS) and overall survivals (OS) of 9.5 and 15.1 months, respectively. Of 43 cases with evaluable bone marrows, cIg-FISH determination of del(13q), t(4;14), t(11;14) and CKS1B amplification was done on 40, 41, 41 and 37 cases and the frequency of their detection was 35%, 15%, 15%, and 32%, respectively. There was no statistically significant difference in response to bortezomib for patients with or without 13q deletion (77% versus 50%), t(4;14) (67% versus 56%), t(11;4) (33% versus 62%), or CKS1B amplification (67% versus 57%). Furthermore, there was no statistically significant difference in PFS or OS following bortezomib therapy between patients with or without these molecular cytogenetic abnormalities. Our data suggest that, in this pilot study, bortezomib is an effective salvage therapy for refractory/relapsed myeloma, irrespective of genetic risk factors.
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PMID:Bortezomib therapy response is independent of cytogenetic abnormalities in relapsed/refractory multiple myeloma. 1699 89

A specific role for increased level of expression of CKS1B, as a consequence of chromosome 1q21 copy number gain, has been postulated as both pathogenic, as well as a powerful clinical prognostic factor in multiple myeloma (MM). The purpose of this study is to determine the clinical associations and prognostic impact of copy number gain at chromosome 1q21 (with a bacteria artificial chromosome clone containing CKS1B) and CKS1B gene level of expression in MM. We studied the chromosome region 1q21 for copy number change in a cohort of myeloma patients treated by high-dose therapy with stem-cell rescue (HDT) (n = 159). A separate cohort of patients, treated by HDT was studied for CKS1B messenger RNA expression by gene expression profiling (n = 67). 1q21 gain was then correlated with clinical parameters and survival. Gain of 1q21 copy number was detected in about a third of MM and was associated with more proliferative disease and poor-risk cytogenetic categories such as t(4;14), and chromosome 13 deletion. Both 1q21 gain and increase gene expression level were significantly associated with reduced survival. However, neither is an independent prognostic marker in MM on multivariate Cox proportional hazard analysis.
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PMID:Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma. 1702 18

Overexpression of CKS1B, a gene mapping within a minimally amplified region between 153 to 154 Mb of chromosome 1q21, is linked to a poor prognosis in multiple myeloma (MM). CKS1B binds to and activates cyclin-dependent kinases and also interacts with SKP2 to promote the ubiquitination and proteasomal degradation of p27(Kip1). Overexpression of CKS1B or SKP2 contributes to increased p27(Kip1) turnover, cell proliferation, and a poor prognosis in many tumor types. Using 4 MM cell lines harboring MAF-, FGFR3/MMSET-, or CCND1-activating translocations, we show that lentiviral delivery of shRNA directed against CKS1B resulted in ablation of CKS1B mRNA and protein with concomitant stabilization of p27(Kip1), cell cycle arrest, and apoptosis. Although shRNA-mediated knockdown of SKP2 and forced expression of a nondegradable form of p27(Kip1) (p27(T187A)) led to cell cycle arrest, apoptosis was modest. Of importance, while knockdown of SKP2 or overexpression of p27(T187A) induced cell cycle arrest in KMS28PE, an MM cell line with biallelic deletion of CDKN1B/p27(Kip1), CKS1B ablation induced strong apoptosis. These data suggest that CKS1B influences myeloma cell growth and survival through SKP2- and p27(Kip1)-dependent and -independent mechanisms and that therapeutic strategies aimed at abolishing CKS1B function may hold promise for the treatment of high-risk disease for which effective therapies are currently lacking.
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PMID:CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms. 1730 95

Multiple myeloma (MM) is the second most common hematological malignancy and remains incurable. The marked variation in survival of patients with symptomatic myeloma ranging from few months to more than 15 years can be explained by differences in tumor mass, proliferative activity and, more recently, by cytogenetic and molecular genetic characteristics of the myeloma clone. Oligonucleotide microarray-based gene expression analysis was applied to CD138-enriched plasma cells from newly diagnosed patients with symptomatic or progressive multiple myeloma treated with melphalan-based high-dose therapy. Here we discuss recent progress made in the development of molecular-based diagnostics and prognostics for MM from Myeloma Institute for Research and Therapy of University Arkansas for Medical Sciences, where we treat more patients with myeloma than anywhere else in the world. Seven distinct entities of myeloma were elucidated by genomic profiling. Expression extremes of 70 genes from a high-risk signature profile,30% of which were derived from chromosome 1, were strongly linked to disease-related survival. CKS1B located on chromosome 1q21, responsible for promoting cell cycle progression by inducing the degradation of p27Kip1, represented a strong candidate gene related to rapid patient death and was studied in detail. The data suggest that CKS1B influences myeloma cell growth and survival through SKP2j and P27(Kip1) -dependent and independent mechanisms and that therapeutic strategies aimed at abolishing CKS1B function may hold promise for the treatment of high-risk disease for which effective therapies are currently lacking.
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PMID:Gene expression profiling defines a high-risk entity of multiple myeloma. 1747 23

The combination of fluorescence in situ hybridization with cytoplasmic light chain detection identified chromosome 1p21 deletion in 18 (20%) of 87 patients with multiple myeloma. 1p21 deletion was associated with higher serum calcium level, 13q deletion, and t(4;14). Patients with 1p21 deletions had a significantly shorter progression-free survival (PFS) (median 10.5 vs. 22.3 months, P = 0.0002) and shorter overall survival (OS) (median 33.9 months vs. not reached, P = 0.002) than those without 1p21 deletions. On multivariate analysis, which included deletions of 13q, TP53, t(4;14) and CKS1B amplification, 1p21 deletion remained as an independent risk factor for PFS (P = 0.01) and OS (P = 0.04).
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PMID:Chromosome 1p21 deletion is a novel prognostic marker in patients with multiple myeloma. 1785 6


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