Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To study the structural integrity of the cyclin-dependent kinase inhibitors known as INK4A (p16), INK4B (p15) and INK4C (p18) in multiple myeloma, we examined 20 primary myeloma samples (including one case of plasma cell leukaemia) using polymerase chain reaction-single strand conformation polymorphism, and 17 samples were examined by Southern blot analysis. The plasma cell leukaemia sample had homozygous deletions of the p15 and p16 genes (6%). One myeloma case had a p15 gene homozygous deletion (6%) with an intact p16 gene. This sample also had a p18 homozygous deletion, suggesting that the deletion of both genes may be important in either the development or progression of myeloma. No point mutations of these INK4 genes were found in the 20 samples. This is the first report that indicates that deletions of p15, p16 and p18 genes occur in some individuals with multiple myeloma (2/17 cases).
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PMID:Analysis of the p16INK4A, p15INK4B and p18INK4C genes in multiple myeloma. 901 94

The INK4A/ARF locus yields two tumor suppressors, p16INK4A and p14ARF, and is frequently deleted in human tumors. We studied their mRNA expressions in 41 hematopoietic cell lines and in 137 patients with hematological malignancies; we used a quantitative reverse transcription-PCR assay. Normal peripheral bloods, bone marrow and lymph nodes expressed little or undetectable p16INK4A and p14ARF mRNAs, which were readily detected in 12 and 17 of 41 cell lines, respectively. Patients with hematological malignancies frequently lacked p16INK4A expression (60/137) and lost p14ARF expression less frequently (19/137, 13.9%). Almost all patients without p14ARF expression lacked p16INK4A expression, which may correspond to deletions of the INK4A/ARF locus. Undetectable p16INK4A expression with p14ARF expression in 41 patients may correspond to p16INK4A promoter methylation or to normal expression status of the p16INK4A gene. All patients with follicular lymphoma (FL), myeloma or acute myeloid leukemia (AML) expressed p14ARF while nine of 23 patients with diffuse large B cell lymphoma (DLBCL) lost p14ARF expression. Patients with ALL, AML or blast crisis of chronic myelogenous leukemia expressed abundant p16INK4A mRNAs more frequently than patients with other diseases (12/33 vs 6/104, P < 0.01). Patients with FL and high p14ARF expression had a significantly shorter survival time while survival for patients with DLBCL and increased p14ARF expression tended to be longer. These observations indicate that p16INK4A and p14ARF expression is differentially affected among hemato- logical malignancies and that not only inactivation but also increased expression may have clinical significance.
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PMID:Expression of p16INK4A and p14ARF in hematological malignancies. 1055 50

p15(INK4b) and p16(INK4a) proteins are cell cycle regulators involved in the inhibition of G1 phase progression. High frequency of methylation of both genes has been reported in multiple myeloma (MM), but it remains to be determined how and when these alterations contribute to tumorigenesis. Monoclonal gammopathy of undetermined significance (MGUS) represents an early disease stage in a fraction of MMs. Plasma cells from 33 patients with MGUS and 33 patients with MM were isolated and analyzed for p15(INK4b) and p16(INK4a) methylation by methylation-specific polymerase chain reaction. Selective methylation was found in 19% for p16(INK4a), 36% for p15(INK4b), and 6.5% for both genes in MGUS, and frequencies were similar in MM suggesting that methylation of these genes is an early event, not associated with transition from MGUS to MM. p15(INK4b) and p16(INK4a) gene methylation might contribute to immortalization of plasma cells rather than malignant transformation in the natural history of MM.
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PMID:p16(INK4a) and p15(INK4b) gene methylations in plasma cells from monoclonal gammopathy of undetermined significance. 1141 89

Methylation of the p16 (INK4a) tumor suppressor gene is observed frequently in multiple myeloma and various forms of lymphoma and mediates silencing of p16 gene expression. In this investigation, we have determined the effect of the DNA demethylating drug decitabine (DAC; 5-aza-2'-deoxycytidine) on the growth, cell cycle kinetics, RB phosphorylation, and expression of p16 (INK4a) and p21(WAF1) in EBV- human myeloma and EBV+ lymphoblastic cell lines possessing silenced, methylated p16 (INK4a) genes to: (1). evaluate its potential as a therapeutic agent and (2). investigate its mechanism of action. Demethylation of the p16 (INK4a) gene and expression of the p16 (INK4a) protein were observed using higher doses (10(-6)-10(-7)M) of drug while growth inhibition at lower doses (IC(50)=2 x 10(-8)-4 x 10(-8)M) was associated with RB dephosphorylation and increased expression of p21 (WAF1), but not with induction of p16 (INK4a), or apoptosis. Kinetic experiments demonstrated that RB dephosphorylation and the increase of p21 (WAF1) preceded the induction of p16 (INK4a). The drug induced cell cycle arrest at the G1 and G2/M phases. Antisense experiments demonstrated that the G1 arrest was mediated by transcriptional induction of p21(WAF1). In addition to these observed effects on cell cycle regulatory proteins, decitabine also increased phosphorylation of p38 MAP kinase. The G2/M arrest was inhibited by the p38 MAP kinase inhibitor SB203580, indicating that activation of p38 MAP kinase pathway was required for G2/M arrest. Thus, decitabine inhibited growth by inducing cell cycle arrest at the G1 phase mediated by p21(WAF1) and the G2/M phase through activation of the p38 MAP kinase pathway.
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PMID:Decitabine induces cell cycle arrest at the G1 phase via p21(WAF1) and the G2/M phase via the p38 MAP kinase pathway. 1285 93

In the detection of DNA hypermethylation as a tumor-specific epigenetic change in blood mononuclear cell fraction in patients with lymphoid and hematopoetic disorders, circulating tumor cells originating from the lymph nodes or bone marrow can be identified. However, it is still not clear whether methylation in mononuclear cells is disease specific. In the present study, we investigated whether methylation of the inhibitor of cyclin-dependent kinase (INK) 4A/alternative reading frame (ARF) locus is present in a disease-specific manner in the blood mononuclear cell fraction of patients with lymphoma, multiple myeloma, or leukemia. To increase the sensitivity of detection, a two-step methylation-specific PCR approach was used to analyze the methylation status of the promoter/exon 1 regions of both p14ARF and p16INK4A genes. Our findings indicate that although INK4A/ARF locus methylation is present in mononuclear cells, this event is not disease-specific since normal subjects also display methylated DNA in their mononuclear cells. In 85.1% of the patients and in 89% of the controls, p16INK4A gene was methylated, while the methylation rates for the p14ARF gene was 32.6 and 36.5%, respectively. The presence of methylated CpG sites in DNA in samples from normal subjects was confirmed by bisulfite genomic sequencing. The difference in the methylation rate between p16INK4A and p14ARF genes among the patients was highly significant (p<0.001). Our results demonstrate that methylation of the INK4A/ARF locus is not a disease-specific molecular change in mononuclear cell fraction and that the p14ARF and p16INK4A genes are differentially methylated.
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PMID:Methylation of the INK4A/ARF locus in blood mononuclear cells. 1632 52

Accumulating evidences suggest that many molecules are working as inhibitors of proliferation in myeloma cells e.g., PTEN, mTOR(PI3-kinase signal molecules), p53, RB1, INK4 family and KIP/CIP family (cell cycle check point molecules), PF4 (inhibitor of angiogenesis). In this review, significance of these molecules in myeloma is summarized. Additionally, our finding of growth inhibitory effect by PU.1 is explained.
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PMID:[Molecular mechanisms inhibiting proliferation of myeloma cells]. 1806 60

Plasma cell leukemia (PCL) is an aggressive and rare hematological malignancy that originates either as primary disease (pPCL) or as a secondary leukemic transformation (sPCL) of multiple myeloma (MM). We report here the genetic aberrations and survival of 80 patients with pPCL or sPCL and make comparisons with 439 cases of MM. pPCL presents a decade earlier than sPCL (54.7 vs 65.3 years) and is associated with longer median overall survival (11.1 vs 1.3 months; P<0.001). 14q32 (IgH) translocations are highly prevalent in both sPCL and pPCL (82-87%); in pPCL IgH translocations almost exclusively involve 11q13 (CCND1), supporting a central etiological role, while in sPCL multiple partner oncogenes are involved, including 11q13, 4p16 (FGFR3/MMSET) and 16q23 (MAF), recapitulating MM. Both show ubiquitous inactivation of TP53 (pPCL 56%; sPCL 83%) by coding mutation or 17p13 deletion; complemented by p14ARF epigenetic silencing in sPCL (29%). Both show frequent N-RAS or K-RAS mutation. Poor survival in pPCL was predicted by MYC translocation (P=0.006). Survival in sPCL was consistently short. Overall pPCL and sPCL are different disorders with distinct natural histories, genetics and survival.
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PMID:Genetic aberrations and survival in plasma cell leukemia. 1821 67

Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes (P < 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was SPIB, which encodes an ETS family transcription factor. Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the INK4a/ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype. FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17-92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways.
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PMID:Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. 1876 95

Multiple myeloma (MM) is an incurable plasma cell neoplasm. Pathogenesis involves upregulation of D-type cyclins and activation of oncogenes, but little is known about the role of tumor suppressor genes. Gene hypermethylation is an alternative mechanism of tumor suppressor gene inactivation. Various approaches have been used to elucidate the role of gene hypermethylation in MM, including a candidate gene approach, microarray approach for genes upregulated by hypomethylating agents, and a cancer pathway approach, which enables a comprehensive picture of the involvement of multiple tumor suppressor genes in MM. Based on the cancer pathway approach, the following data on the involvement of cell cycle control, intrinsic tumor suppressor, and cell signaling were derived. First, among the INK4 and CIP/KIP families of cyclin-dependent kinase inhibitors, only CDKN2B and CDKN2A are frequently hypermethylated. Second, methylation of SHP1 and soluble Wnt inhibitors is associated with constitutive activation of JAK/STAT and Wnt signaling. Importantly, downregulation of the signaling pathways can be restored by demethylation and re-expression of SHP1 and soluble Wnt inhibitors, which is potentially important therapeutically. Third, of the tumor suppressor genes involved in the DAPK/P14/HDM2/P53/Apaf-1 pathway, only DAPK is frequently methylated, which appeared to be an adverse prognostic factor to survival. Lastly, apart from being implicated in the progression from monoclonal gammopathy of unknown significance to MM, aberrant gene promoter methylation might also account for late disease progression in MM. Future studies are needed to delineate the biologic consequence of gene hypermethylation, the prognostic effect of gene methylation, and the possibility of hypomethylation therapy.
Clin Lymphoma Myeloma 2008 Dec
PMID:Gene hypermethylation in multiple myeloma: lessons from a cancer pathway approach. 1906 97

Multiple myeloma (MM) is an incurable hematological malignancy. Different studies demonstrated the occurrence of genetic and epigenetic alterations in MM. The aberrant methylation is one of the most frequent epigenetic alterations in human genome. This study evaluated the aberrant methylation status of 20 genes in 51 MM samples by quantitative methylation-specific PCR (QMSP) and compared the methylation profile with clinicopathological characteristics of the patients. The QMSP analyses showed that PTGS2 (100.0%), SFN (100.0%), CDKN2B (90.2%), CDH1 (88.2%), ESR1 (72.5%), HIC1 (70.5%), CCND2 (62.7%), DCC (45.1%) and TGFbetaR2 (39.2%) are frequently hypermethylated in MM while aberrant methylation of RARbeta (16.6%), MGMT (12.5%), AIM1 (12.5%), CDKN2A (8.3%), SOCS1 (8.3%), CCNA1 (8.3%) and THBS1 (4.1%) are rare events. There was no methylation of GSTP1, MINT31, p14ARF and RB1 in the samples tested. Hypermethylation of ESR1 was correlated positively with isotype IgA, while aberrant methylation of THBS1 correlated negatively with isotype IgG. Furthermore, hypermethylation of DCC and TGFbetaR2 were correlated with poor survival. The multivariate analysis showed ISS and TGFbetaR2 hypermethylation strongly correlated with poor outcome. This study represents the first quantitative evaluation of promoter methylation in MM and our data provide evidence that TGFbetaR2 hypermethylation, besides ISS, may be useful as prognostic indicator in this disease.
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PMID:TGFbetaR2 aberrant methylation is a potential prognostic marker and therapeutic target in multiple myeloma. 1954 9


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