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PubMed2000

The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses.

Interleukin 6 (IL-6) and insulin-like growth factor I (IGF-I) induce proliferative and antiapoptotic responses in multiple myeloma (MM) plasma cells. Because these cytokines may activate the phosphatidylinositol 3-kinase (PI 3-K)/AKT kinase pathway in other cell types, we investigated the role of PI 3-K/AKT in MM cell responses. IGF-I effectively activated PI 3-K in 8226 and OCI-My5 MM cells, but IL-6 was ineffective. However, IL-6 successfully activated PI 3-K in AF-10 MM cells and IL-6-dependent MH.60 plasmacytoma/hybridoma cells. IGF-I also successfully activated PI 3-K in four of four MM patient specimens, and IL-6 activated PI 3-K in three of four specimens. Inhibition of PI 3-K activity with wortmannin or Ly294002 blocked the antiapoptotic effect of IGF-I and the proliferative effect of IL-6 in the myeloma cell lines. Furthermore, a dominant negative PI 3-K construct, expressed in AF-10 cells by adenoviral infection, also significantly inhibited the IL-6 proliferative response in MM cells. In correlation with activation of PI 3-K, IGF-I also effectively activated the AKT kinase in 8226 and OCI-My5 cells, and IL-6 activated AKT in AF-10 and MH.60 cells. However, although incapable of activating PI 3-K in 8226 and OCI-My5 cells, IL-6 successfully activated AKT in these MM lines, suggesting PI 3-K-independent mechanisms of AKT activation. The prevention of a myeloma cell proliferative response resulting from inhibition of PI 3-K activity was not associated with an inhibition of IL-6-dependent extracellular signal-regulated kinase (ERK) activation. These results support a role for the PI 3-K/AKT pathway in cytokine-dependent responses in myeloma cells, which is independent of any activation of the ERK pathway.

Androstadienes↗
PubMed1986

Multiple myeloma plasma cell kinetics: rapid and reliable evaluation using 5-bromo-2-deoxyuridine (BrdUrd) DNA incorporation detected by an anti-BrdUrd monoclonal antibody.

In 19 patients with monoclonal gammopathy, plasma cell proliferative activity was evaluated using 5-bromo-2-deoxyuridine (BrdUrd) incorporation, as revealed by an anti-BrdUrd monoclonal antibody. A simultaneous standard labelled thymidine incorporation was carried out in all patients as reference test. The BrdUrd method was confirmed as a reliable test and is recommended for routine clinical application in monoclonal gammopathies.

Antibodies, Monoclonal↗
PubMed1994

Plasma cell myeloma in patients who are HIV-positive.

This report describes the occurrence of plasma cell neoplasia in three young HIV-positive males. Two patients presented with massive ascites. On cytologic examination of the fluid, many immature plasma cells were noted. Genotyping of fluid demonstrated clonal rearrangement of immunoglobulin heavy and kappa light chain genes in both cases. Postmortem examination on one of these revealed neoplastic plasmacellular infiltrate in various organs, including the bone marrow. The third case presented with a hemorrhagic, rapidly enlarging gingival mass with a histologic appearance of an undifferentiated neoplasm. Immunoperoxidase studies revealed positive staining only for epithelial membrane antigen. On flow cytometry, the neoplastic cells did not mark with leukocyte common antigen or any of the B- or T-cell markers. Cytoplasmic kappa light chain restriction, as well as genotypic studies, confirmed the diagnosis of anaplastic plasmacytoma. In two cases a clonal population was detected using a probe to the terminal repeat region of the Epstein-Barr virus. These results suggest that plasma cell malignancy is another AIDS-associated neoplasm. Its occurrence in this group of patients is not only coincidental.

Adult↗
PubMed2005

Blockade of the Ras pathway by manumycin, a farnesyltransferase inhibitor, overcomes the resistance of myeloma plasma cells to Fas-induced apoptosis.

Ras activation (by point mutation or binding of IL-6) is frequently observed in multiple myeloma (MM). As farnesylation of Ras protein by farnesyltransferase is a critical step for Ras functional activity, farnesyltransferase inhibitors (FTI) have emerged as potential anti-cancer agents. Manumycin, a natural FTI, prevents proliferation and induces apoptosis of myeloma cells refractory to Fasand drug-induced cell death. Fas pathway analysis showed that Fas-resistant apoptosis of Fas-positive myeloma cells parallels FLIP (FLICE/caspase-8-inhibitory protein) expression. Treatment of fresh purified myeloma cells, myeloma cell clone-2 and U266 cell line with manumycin induced down-regulation of FLIP expression with concomitant expression of Apo 2.7 antigen, the marker of early apoptosis. Down-regulation of FLIP mRNA levels in drug-treated cells was associated to suppression of the transcription factor NF-kappaB that plays a central role in chemoresistance, survival and proliferation of myeloma cells. Further analysis showed that manumycin-induced apoptosis involved caspases activation and was prevented by the addition of caspases specific inhibitors. Finally, pretreatment of Fas-resistant/FLIP-positive cells with manumycin sensitised them to Fas-triggered apoptosis. Overall results indicate that manumycin-induced apoptosis involves Fas pathway. FTIs may thus be proposed as a promising class of anti-cancer agents which can boost the cytotoxic effect of conventional drugs by overcoming NF-kappaB activation and Fas-resistant apoptosis.

Apoptosis↗
PubMed2003

In vivo time-course of the angiogenic response induced by multiple myeloma plasma cells in the chick embryo chorioallantoic membrane.

In this study, we set out to make a fine characterization of the angiogenic response induced by plasma cells obtained from patients with active-multiple myeloma (MM), in comparison with cells obtained from patients with non-active MM and benign lesions such as monoclonal gammopathy of undetermined significance (MGUS), in the chick embryo chorioallantoic membrane (CAM) assay. To achieve this we investigated the time-course of the angiogenic response induced by gelatin sponges soaked in the cell suspensions and implanted on the CAM surface from day 8 to day 12 of incubation by evaluating the number of vessels, of the vessel bifurcation and the intervascular distance at 24, 48, 72 and 96 h after the implants. The results show that plasma cell suspensions obtained from patients with active MM induce a vasoproliferative response that was significantly higher than that induced by cell suspensions obtained from patients with non-active MM or with MGUS, which is also a function of the day of implantation. In fact, implants made from day 8 to day 10 induce a strong angiogenic response, whereas those made from day 11 to day 12 do not. This finding might depend on the fact that CAM endothelium exhibits an intrinsically high mitotic rate until day 10. Thereafter, the endothelial mitotic index declines rapidly, and consequently cell suspensions implanted on the CAM of successively older embryos are not able to induce a vasoproliferative response in parallel with the reduced rates of growth of the CAM's endothelial cells.

Allantoin↗
PubMed2006

The expression of PRDI-BF1 beta isoform in multiple myeloma plasma cells.

The PRDM1 gene, a master regulator of plasma cells (PC), can generate two transcription factor isoforms: PRDI-BF1alpha and PRDI-BF1beta. The present study shows that purified human normal PC have a significantly lower levels of PRDI-BF1beta expression than that in tumoral PC isolated from multiple myeloma (MM) (0.06+/-0.01 and 0.25+/-0.05, respectively; p<0.001). The role of this finding in MM is discussed.

Gene Expression Regulation, Neoplastic↗
PubMed1976

Monoclonal B-lymphocytes in peripheral blood of patients with plasma cell myeloma. Relation to activity of the disease.

Antisera were produced in rabbits against idiotypic determinants of the myeloma protein from 3 patients with IgG-k myeloma. The antisera did neither cross-react nor react with normal immunoglobulin (Ig). Idiotypic Ig-structures were demonstrated by indirect immunofluorescence (IFL) on 70-94% of peripheral B-lymphocytes inuntreated patients. The total numbers of circulating B-lymphocytes were increased with a simultaneous decrease of T-lymphocytes. Only one of the patients had blood lymphocytes which stained for cytoplasmic Ig with idiotypic antiserum. The monoclonal lymphocyte population decreased gradually during treatment. Plasma cell counts in bone marrow, IgG concentration in serum and erythrocyte sedimentation rate decreased simultaneously, whilt the haemoglobin concentration increased. Very few monoclonal lymphocytes were present during remission. Later, the monoclonal lymphocyte population began to increase in 2 of the patients in parallel with clinical signs indicating relapse. It is concluded that presence of monoclonal B-lymphocytes indicates dissemination of the disease and that they may belong to the malignant cell clone.

B-Lymphocytes↗
PubMed2003

Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels.

HMG-CoA reductase is the rate-limiting enzyme of the mevalonate pathway leading to the formation of cholesterol and isoprenoids such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP). The inhibition of HMG-CoA reductase by lovastatin induced apoptosis in plasma cell lines and tumor cells from patients with multiple myeloma. Here we show that cotreatment with mevalonate or geranylgeranyl moieties, but not farnesyl groups, rescued myeloma cells from lovastatin-induced apoptosis. In addition, the inhibition of geranylgeranylation by specific inhibition of geranylgeranyl transferase I (GGTase I) induced the apoptosis of myeloma cells. Apoptosis triggered by the inhibition of geranylgeranylation was associated with reduction of Mcl-1 protein expression, collapse of the mitochondrial transmembrane potential, expression of the mitochondrial membrane protein 7A6, cytochrome c release from mitochondria into the cytosol, and stimulation of caspase-3 activity. These results imply that protein geranylgeranylation is critical for regulating myeloma tumor cell survival, possibly through regulating Mcl-1 expression. Our results show that pharmacologic agents such as lovastatin or GGTase inhibitors may be useful in the treatment of multiple myeloma.

Alkyl and Aryl Transferases↗
PubMed1977

Differentiation of plasma and myeloma cells of man. Combined planimetric and cytophotometric studies.

Plasmacytoid cells in the bone marrow of 3 patients with myeloma and plasma cells in the bone marrow of a 6-year-old boy with an infectious disease were assessed cytophotometrically, first after Giemsaand second after Feulgen staining. The cell and nuclear surface and the nuclear/cytoplasmic ratio were determined from the number of measuring points. The nuclear DNA content of individual cells was registered and the distribution of DNA within the nucleus was assessed by the distributional error. Both the mean nuclear/cytoplasmic ratio and the distributional error of myeloma cells varied from patient to patient but could not be used to differentiate between normal plasma cells and myeloma cells. It was not possible either to differentiate these cell types by multiplying the mean nuclear/cytoplasmic ratio with the mean distributional error of the nuclear DNA. A strong correlation between cell and cytoplasmic surface area was observed both in normal plasma cells and in myeloma cells.

Bone Marrow↗
PubMed1980

Immunoglobulin isotypes on monoclonal blood lymphocytes in human plasma cell myeloma.

Purified blood lymphocytes from 30 patients with myelomatosis were studied. B lymphocytes with sIg were identified by direct IFL after staining with F(ab')2-fragments of antibodies against heavy or light chain specificities. Forty per cent of the patients had B lymphocyte values above the normal range; the median percentage of B cells was 7.25 as compared to 4.5 for control donors (p less tha 0.01). Lymphocytes bearing the light chain isotype of the myeloma protein were selectively increased in 20 of 30 patients suggesting monoclonality. The heavy chain specificities on such lymphocytes were usually that of the serum myeloma globulin sometimes together with mu and/or delta. Tentatively, mu and/or delta carrying monoclonal lymphocytes may represent early precursors to the malignant plasma cells. In patients with IgG myelomas, gamma-bearing blood lymphocytes may be late during maturation. The presence of monoclonal lymphocytes with surface bound gamma chains in untreated patients was associated with unfavourable prognosis.

Adult↗
PubMed1987

Delineation of a novel pre-B cell component in plasma cell myeloma: immunochemical, immunophenotypic, genotypic, cytologic, cell culture, and kinetic features.

A novel pre-B cell component in direct and cultured myeloma bone marrow material has been delineated by using immunochemistry and flow cytometry techniques. Our phenotypic studies suggest a novel hybrid expression of pre-B and plasma cell antigens with coexpression of cytoplasmic mu, common acute lymphoblastic leukemia antigen, terminal deoxynucleotidyl transferase, and plasma cell antigens (PCA-1 and PC-1). This suggests that myeloma pre-B-like cells are aberrant malignant cells and not normal pre-B lymphocytic counterparts. With the advantage of a pure and stable source of these cells from M3 culture to allow molecular characterization, we performed one- and two-dimensional gel electrophoresis and Western blotting. We found that the cytoplasmic mu in myeloma pre-B-like cells has a molecular weight of 74,000 daltons and an isoelectric point of 6.3 and that it is strikingly homogeneous and discrete in size and charge compared with standard secretory mu, which suggests an aberrant, mutant, or monoclonal form of mu. Monoclonality was further evidenced by heavy- and light-chain immunoglobulin gene rearrangements demonstrated with JH and C kappa probes. We also established that this novel myeloma pre-B component is a major proliferative element as determined by double-labeling experiments with phenotype coupled to labeling/proliferative indexes. Our stimulatory studies indicate some capacity of these cells to mature on exposure to phorbol esters. These myeloma pre-B cells may represent the stem cell or self-renewal component in myeloma. Our establishment of these cells in long-term culture offers a considerable asset in studying the immature cells, which may be critical to the immortalization of myeloma.

B-Lymphocytes↗
PubMed1986

Establishment and characterization of a human plasma cell myeloma culture having a rearranged cellular myc proto-oncogene.

Using a serum-free defined medium, we have established a human cell line, NCI-H929, from a malignant effusion occurring in a patient with IgAk myeloma. The cultured cells have the morphologic, ultrastructural, biochemical, immunologic, and cytochemical features of plasma cells. The cells have rearranged alpha and kappa genes and synthesize and secrete high amounts of IgAk (greater than 80 micrograms/10(6) cells per 24 hours). The cells express surface immunoglobulin (alpha and kappa), the plasma cell antigen PCA-1, the transferrin receptor (T9) and T10 but lack antigens associated with earlier stages of B cell development (HLA-DR, B1, B2, B4, CALLA), as well as other leukocyte-macrophage antigens and Epstein-Barr virus (EBV) nuclear antigen. Although molecular studies confirm that both the tumor and cultured cells are derived from the same clone of malignant B cells, the tumor cells were predominantly near-diploid, whereas the cultured cells are predominantly near-tetraploid with six copies of chromosome 8, four to six of which have an 8q + abnormality. However, both the tumor and the cultured cells have a rearrangement of the cellular c-myc proto-oncogene (located at 8q24) and express c-myc RNA. Although a modest number of human "plasmacytoid" cell lines have been established, most are lymphoblastoid lines lacking plasma cell features, while others appear to be early secretory cells. In contrast, NCI-H929 is a differentiated, highly secretory human plasma cell line.

B-Lymphocytes↗