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

Multiple myeloma (MM) is a malignant proliferation of bone marrow plasma cells. Molecular analyses of the involvement of oncogenes (c-myc, and N- and K-ras genes) and suppressor gene (p53) in pathogenesis of MM have been recently carried out. Relatively high incidence of elevated expression of c-myc mRNA have been found, although the gene rearrangements are very rare. Mutations of N- and K-ras genes have been found in about 1/3 of patients with MM. Point mutations of p53 gene were detected in about 10-20% of patients. The mutations were found in terminal or leukemic phase of the disease. These indicate that oncogenes and suppressor genes are involved in the development and progression of MM.
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PMID:[Molecular analysis of multiple myeloma cells]. 769 86

Transcobalamin II (TCII) is a plasma protein that binds vitamin B12 (cobalamin; Cbl) and facilitates the cellular uptake of the vitamin by receptor-mediated endocytosis. In genetic disorders that are characterized by congenital deficiency of TCII, intracellular Cbl deficiency occurs, resulting in an early onset of megaloblastic anemia that is sometimes accompanied by a neurologic disorder. To define the genetic basis for TCII deficiency, we have cloned and characterized the human gene that encodes this protein. The gene spans a minimum of 18 kbp and contains nine exons and eight introns, with a polyadenylation signal sequence located 509 bp downstream from the termination codon and a transcription initiation site beginning 158 bp upstream from the ATG translation start site. The 5' flanking DNA does not have a TATA or CCAAT regulatory element, but a 34-nucleotide stretch beginning just upstream of the CAP site contains four tandemly organized 5'-CCCC-3' tetramers. This sequence is a motif for a trans-active transcription factor (ETF) that regulates expression of the epidermal growth factor receptor gene (EGFR), which also lacks TATA and CCAAT regulatory elements. A GC-rich sequence that binds the SP1 protein is located 356 nucleotides upstream from the first of the series of CCCC tetramers. Although this GC sequence is at an unusual location with respect to the CAP site, a 507-bp fragment containing this GC box drives the chloramphenicol acetyltransferase (CAT) reporter gene after transient transfection into NIH 3T3 cells. No CAT activity was observed when a 420-bp fragment lacking this GC box but containing the ETF-binding domains was similarly transfected into this cell line. One consensus and two atypical motifs for the c-myc ligand are located downstream and upstream, respectively, of the GC box, and this could explain the elevated plasma TCII observed in some patients with multiple myeloma, as the c-myc product is overexpressed in some myeloma cells. Restriction endonuclease digestion of genomic DNA from eight normal subjects with Taq I, Hinfl, Msp I, and Bgl I identified three patterns of restriction fragment length polymorphism (RFLP). A number of the exon/intron splice junctions of human TCII, TCI, and IF genes are located in homologous regions of these proteins, providing evidence that these genes have evolved by duplication of an ancestral gene. This characterization of the TCII gene and the RFLP should facilitate the identification of the mutation(s) responsible for the genetic abnormalities of TCII expression.
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PMID:The cloning and characterization of the human transcobalamin II gene. 774 31

The posttransplantation lymphoproliferative disorders (PT-LPDs) are a morphologically heterogeneous group of Epstein-Barr virus (EBV)-driven lymphoid proliferations of varying clonal composition. Some PT-LPDs regress after a reduction in immunosuppression, while others progress in spite of aggressive therapy. Previously defined morphologic categories do not correlate with clonality, and neither morphology nor clonality has reliably predicted the clinical behavior of PT-LPDs. We investigated 28 PT-LPD lesions occurring in 22 patients for activating alterations involving the bcl-1, bcl-2, c-myc, and H-, K- and N-ras proto-oncogenes and for mutations involving the p53 tumor suppressor gene. We correlated the results of these studies with the morphology of the lesions, their clonality based on Ig heavy and light chain gene rearrangement analysis, and the presence and clonality of EBV infection. We found that the PT-LPDs are divisible into three distinct categories as follows: (1) plasmacytic hyperplasia: most commonly arise in the oropharynx or lymph nodes, are nearly always polyclonal, usually contain multiple EBV infection events or only a minor cell population infected by a single form of EBV, and lack oncogene and tumor suppressor gene alterations; (2) polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma: may arise in lymph nodes or various extranodal sites, are nearly always monoclonal, usually contain a single form of EBV, and lack oncogene and tumor suppressor gene alterations; and (3) immunoblastic lymphoma or multiple myeloma: present with widely disseminated disease, are monoclonal, contain a single form of EBV, and contain alterations of one or more oncogene or tumor suppressor genes (N-ras gene codon 61 point mutation, p53 gene mutation, or c-myc gene rearrangement). The PT-LPDs are divisible into three categories exhibiting distinct morphologic and molecular genetic characteristics. Alterations involving the N-ras and c-myc proto-oncogenes and the p53 tumor suppressor gene may play an important role in the development and/or progression of the PT-LPDs.
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PMID:Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. 781 11

The expression of nucleoside transporters is a limiting factor in the pharmacology of the nucleoside analogue, cytosine arabinoside (AraC) and is associated with cellular proliferation. We investigated the expression of nucleoside transporters on plasma cells from the bone marrow of 51 patients with multiple myeloma by 2-colour immunofluorescence flow cytometry, utilising 5-(SAENTA-x8)-fluorescein, a fluorescent ligand for the nucleoside transporter and anti-CD38 conjugated to phycoerythrin, as CD38 expression has unique characteristics on plasma cells. Mean nucleoside transporter expression on bone marrow plasma cells from patients with myeloma (1777 +/- 2181 transporters/plasma cell) was not significantly different from expression on plasma cells from normal bone marrow (997 +/- 1096 transporters/plasma cell). However, analysis of disease subgroups revealed a significant trend towards increased transporter expression in patients with progressive disease compared to those with stable disease (chi 2 = 4.0, p < 0.05). Nucleoside transporter expression correlated significantly with the plasma cell labeling index (LI) (r = 0.45, p < 0.01) and serum thymidine kinase levels (r = 0.66, p < 0.01), both markers of cellular proliferation but not with c-myc oncoprotein expression. These findings suggest that flow cytometric measurement of nucleoside transporter expression on plasma cells provides a rapid and convenient measurement of disease activity or quiescence in myeloma.
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PMID:Multiple myeloma: expression of nucleoside transporters on malignant plasma cells and their relationship to cellular proliferation. 806 94

Plasma cell atypia and cell proliferation changes which occur during the progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are accompanied by critical changes in neoplastic plasma cells and marrow stromal cells. Key elements include paracrine secretion of interleukin 6 (IL-6) by marrow stromal cells resulting from interleukin 1 beta (IL-1 beta) secreted by myeloma cells. In addition, there are stable elevated levels of serum soluble IL-6 receptor (sIL-6R) in MM and MGUS. They are higher than levels seen in normals. Oncogenes such as c-myc and ras probably play a major role as do cell adhesion molecules and loss of apoptosis. Immune regulatory cells may also play a role. A key element yet to be clearly defined is delineating the role of circulating plasma cells and their precursors in spreading the disease.
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PMID:Pathogenetic relation between monoclonal gammopathies of undetermined significance and multiple myeloma. 852 Apr 96

A hybridoma producing a polyspecific human monoclonal IgM antibody (named CB03) has been derived from a fusion of mouse myeloma cells with human spleen lymphocytes obtained from an autoimmune patient suffering from chronic idiopathic thrombocytopenia. The antibody was found to be encoded by somatically mutated VHI and VlambdaIII genes. To study the input of mutated complementarity regions (CDRs) into antibody specificity, the antigen binding features of the purified complete IgM antibody were compared with (i) a Fab fragment by hot tryptic digestion and (ii) recombinant monovalent fragments expressed in E. coli. In detail, vectors were constructed encoding for (i) rFab03 and single chain Fv03 fragments containing the VH and VL genes connected by a linker sequence, (ii) scFc1.1. fragments containing the VH germline equivalent and the CB03 wild-type CDR3 region, and (iii) scFv fragments containing the CDR1 and CDR2 in germline configuration and the CDR3 expressed in the CB253 human fetal B cell hybridoma producing a polyspecific IgM antibody. The expression vectors contained at the 3' end either a (His)6 motif allowing purification on Ni(2+)-agarose or a c-myc tag for specifically detecting the expression products by a murine monoclonal antibody. Western blotting and ELISA analyses of the expression products indicate: (i) recombinant Fab fragments were found in the bacterial periplasm in extremely low amounts (1-10 micrograms from 1 litre bacterial culture), (ii) scFv fragments were obtained in suitable amounts from bacterial periplasm (800-1000 micrograms/l), (iii) the monovalent recombinant fragments as well as the Fab obtained by tryptic digestion reflected the polyspecific antigen binding features of the complete IgM antibody, but did bind to the antigens with much lower affinity, and (iv) the CDR3 was found to be of critical importance for the antigen binding pattern of this particular IgM. We discuss the expression of recombinant scFv fragments in E. coli as a suitable method in studying the role of the somatic mutation in autoantibody generation.
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PMID:Expression of monovalent fragments derived from a human IgM autoantibody in E. coli. The input of the somatically mutated CDR1/CDR2 and of the CDR3 into antigen binding specificity. 852 57

We studied the molecular alterations of IL-6R, lck and c-myc genes in the tumour cells of 50 patients with multiple myeloma (MM) and 20 patients with monoclonal gammopathies of undetermined significance (MGUS). Southern blot analysis revealed a 5.3 kb IL-6R amplified band by digestion with EcoRI and HindIII in three MGUS patients, but no IL-6R gene alteration was found in MM patients. BamHI digestion revealed a 6.2 kb rearranged band of the lck gene in two MGUS patients with IL-6R amplification. In one MGUS patient we detected a rearrangement upstream of the lck coding region. Myc rearrangement was observed in three MM and two MGUS patients who showed coexistent lck rearrangement and IL-6R amplification. These molecular alterations were detected in the MGUS patients with an IgA monoclonal component, who showed a rapid progression into aggressive MM. Myc rearrangement seems to be associated with a small group of a clinically aggressive MM at diagnosis, secreting IgA or k light chains. Multiple rearrangements and/or molecular alterations are likely to occur at the time of MGUS-IgA transformation into aggressive MM and myc rearrangement may promote a positive pressure for transformation and progression. MM tumourigenesis remains a heterogenous multistep process involving the deregulation of many genes and gene products.
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PMID:Molecular alterations of IL-6R, lck and c-myc genes in transforming monoclonal gammopathies of undetermined significance. 865 83

A number of studies have indicated that the small nuclear acidic protein prothymosin alpha is associated with cellular-proliferation events. For example, c-myc causes immediate transcriptional activation of prothymosin alpha, and prothymosin alpha antisense oligonucleotides inhibit myeloma cell division. To investigate the regulation of prothymosin alpha, we examined its mRNA and protein levels during the cell cycle of mononuclear cells and fibroblastic cells. We isolated immunoreactive material from cellular extracts and immunolocalized the protein to the nucleus during the cell cycle. We reported here that the material present in the cells is prothymosin alpha rather than the amino-terminal peptide thymosin alpha 1. [3H]Thymidine-incorporation studies associate maximum accumulation of mRNA and protein with the S/G2 phase of the cell cycle. This induction of prothymosin alpha mRNA seems to resemble cyclin B expression and is more pronounced in fibroblasts. Moreover, transient-transfection experiments indicate that transcription factor E2F is a strong positive regulator of the prothymosin alpha gene. Our results are consistent with the hypothesis that prothymosin alpha is involved in proliferation checkpoints of the cell cycle.
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PMID:Regulation of prothymosin alpha during the cell cycle. 870 83

We demonstrate a 10- to 25-fold increase in the amount of c-myc protein in several independent cell lines derived from patients with multiple myeloma (MM). This is not accompanied by a corresponding increase in the overall level of the c-myc mRNA. There is, however, a 3.4-fold increase in the amount of c-myc mRNA associated with the polysomes in these cell lines without any detectable change in either the polysome size or the rate of translation elongation, thus suggesting that there is an increase in the extent of mobilisation of c-myc mRNA to the polysomes in MM. Analysis of the 5' untranslated region of c-myc has revealed the presence of a mutation, in all of the MM cell lines examined, in a region which has been implicated previously in the translational control of this mRNA species. These data suggest aberrant translational control of the c-myc gene in cell lines derived from patients with MM, which may contribute towards pathogenesis of the disease.
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PMID:Aberrant translational control of the c-myc gene in multiple myeloma. 876 Feb 92

Chromosomal translocations or DNA rearrangements affecting c-myc occur in almost all murine plasmacytoma and human Burkitt's lymphoma tumors and are associated with a high incidence of exon 2 missense mutations and selective expression of the affected allele. Screening nine multiple myeloma cell lines, we identified no exon 2 missense mutations but did identify two lines with single, silent mutations in exon 1 and exon 2, respectively. Each of these informative multiple myeloma cell lines selectively expresses only one c-myc allele despite the apparent absence of chromosomal translocations or DNA rearrangements affecting c-myc.
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PMID:Selective expression of one c-myc allele in two human myeloma cell lines. 881 27


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