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)

In this study, we have evaluated the proliferation and the phenotype of human plasma cells of different origins, i.e., from tonsil, peripheral blood, bone marrow as well as plasma cells generated in vitro from memory B cells. We have demonstrated that plasma cells from tonsil, peripheral blood, as well as those generated in vitro, were highly proliferating and presented a homogeneous CD45bright phenotype. In contrast, bone marrow plasma cells were heterogeneous for CD45 expression but their proliferation was restricted to the CD45bright compartment. Subsequently, their CD45 expression decreased with proliferation arrest and final maturation. We also studied the proliferation of abnormal plasma cells, i.e., peripheral blood reactive plasmacytoses and multiple myeloma (MM). All reactive plasmacytoses turned out to be homogeneous expansions of CD45bright plasma cells with unusually high labeling index. In contrast, CD45 expression was heterogeneous in MM as in normal bone marrow. However, a minor CD45bright population was also always the most proliferating one as opposed to a major population of less or non-proliferating myeloma cells characterized by a weaker or a lack of CD45 expression. In conclusion, proliferation is linked to plasma-cell generation and a CD45bright phenotype is the hallmark of the most proliferating normal, reactive as well as malignant plasma cells.
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PMID:Normal and malignant human plasma cells: proliferation, differentiation, and expansions in relation to CD45 expression. 1500 21

The active role of angiogenesis during disease progression is well recognized in solid tumors. In hematologic malignancies such as multiple myeloma (MM), it is not known whether tumor neovascularization is an epiphenomenon or whether it is actively involved in disease progression. At clinical presentation, myeloma disease and the associated angiogenesis are both well established. Here the 5T2MM murine model was used to analyze angiogenesis during preclinical myeloma stages. Bone marrow (BM) of 5T2MM-inoculated mice was analyzed at weekly intervals until the end stage of the disease. Histologic analysis and assessment of microvessel density (MVD) by CD31 staining demonstrated a preangiogenic stage of small tumor aggregates followed by an angiogenic switch and subsequently an angiogenic stage of progressive tumor growth and large, confluent tumor nodules. Flow cytometric analysis that indicated an increase in percentage CD45- MM cells preceded the angiogenic switch. Real-time polymerase chain reaction (RT-PCR) of sorted CD45+ and CD45- MM cells indicated higher vascular endothelial growth factor 120 (VEGF120) and VEGF164 transcripts in CD45- MM cells. VEGF enzyme-linked immunosorbent assay (ELISA) revealed high secretion by CD45- MM cells but no protein secretion by CD45+ MM cells, indicating angiogenic heterogeneity among the MM cells. These data suggest that, like in solid tumors, angiogenic switch and angiogenic heterogeneity exist in MM.
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PMID:Angiogenic switch during 5T2MM murine myeloma tumorigenesis: role of CD45 heterogeneity. 1507 Jun 95

Bone marrow aspirates from 306 patients with multiple myeloma were analyzed by flow cytometric immunophenotyping. The plasma cells (PCs) were identified by their characteristic light scatter distribution and reactivity patterns to CD138, CD38, and CD45. Monoclonality was confirmed by immunoglobulin light chain analysis. The immunophenotypic profile of the PCs was determined with a panel of antibodies. Moderate to bright expression of CD56, CD117, CD20, CD45, and CD52 was detected in 71.7%, 17.8%, 9.3%, 8.8%, and 5.2% of cases, respectively. These antigens were expressed by a distinct subpopulation of the PCs in 6.3%, 2.2%, 3.7%, 2.9%, and 2.6% of additional cases. CD19 was negative in more than 99% of cases. The combination of CD38 and CD138 was superior to CD38 alone for identifying CD45+ myeloma and separating CD20+ myeloma from B-cell lymphoma. PC immunophenotyping might be useful for detecting minimal residual disease in cases with aberrant antigen expression and for selection of therapeutic agents that have specific membrane targets.
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PMID:Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. 1508 Feb 99

HuN901 is a humanized monoclonal antibody that binds with high affinity to CD56, the neuronal cell adhesion molecule. HuN901 conjugated with the maytansinoid N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), a potent antimicrotubular cytotoxic agent, may provide targeted delivery of the drug to CD56 expressing tumors. Based on gene expression profiles of primary multiple myeloma (MM) cells showing expression of CD56 in 10 out of 15 patients (66.6%) and flow cytometric profiles of MM (CD38(bright)CD45(lo)) cells showing CD56 expression in 22 out of 28 patients (79%), we assessed the efficacy of huN901-DM1 for the treatment of MM. We first examined the in vitro cytotoxicity and specificity of huN901-DM1 on a panel of CD56(+) and CD56(-) MM cell lines, as well as a CD56(-) Waldenstrom's macroglobulinemia cell line. HuN901-DM1 treatment selectively decreased survival of CD56(+) MM cell lines and depleted CD56(+) MM cells from mixed cultures with a CD56(-) cell line or adherent bone marrow stromal cells. In vivo antitumor activity of huN901-DM1 was then studied in a tumor xenograft model using a CD56(+) OPM2 human MM cell line in SCID mice. We observed inhibition of serum paraprotein secretion, inhibition of tumor growth, and increase in survival of mice treated with huN901-DM1. Our data therefore demonstrate that huN901-DM1 has significant in vitro and in vivo antimyeloma activity at doses that are well tolerated in a murine model. Taken together, these data provide the framework for clinical trials of this agent to improve patient outcome in MM.
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PMID:In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine against CD56+ multiple myeloma cells. 1523 75

In multiple myeloma, the Akt/PI3K pathway is involved in the proliferation of myeloma cells. In the current study, we have investigated the impact of the CD45 phosphatase in the control of Akt/PI3K activation. We show that Akt activation in response to insulin-like growth factor-1 (IGF-1) is highly variable from one human myeloma cell line to another one. Actually, Akt activation is highly related to whether CD45 is expressed or not. Indeed, both the magnitude and the duration of Akt phosphorylation in response to IGF-1 are more important in CD45- than in CD45+ myeloma cell lines. We next demonstrate a physical association between CD45 and IGF-1 receptor (IGF-1R) suggesting that CD45 could be involved in the dephosphorylation of the IGF-1R. Furthermore, the growth of CD45- myeloma cell lines is mainly or even totally controlled by the PI3K pathway whereas that of CD45+ myeloma cell lines is modestly controlled by it. Indeed, wortmannin, a specific PI3K inhibitor, induced a dramatic growth inhibition in the CD45- myeloma cell lines characterized by a G1 growth arrest, whereas it has almost no effect on CD45+ myeloma cell lines. Altogether, these results suggest that CD45 negatively regulates IGF-1-dependent activation of PI3K. Thus, strategies that block IGF-1R signaling and consequently the Akt/PI3K pathway could be a priority in the treatment of patients with multiple myeloma, especially those lacking CD45 expression that have a very poor clinical outcome.
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PMID:The magnitude of Akt/phosphatidylinositol 3'-kinase proliferating signaling is related to CD45 expression in human myeloma cells. 1547 37

CD45, a receptor-type tyrosine phosphatase, is required for interleukin-6 (IL-6)-induced proliferation in human myeloma cells, which express the shortest isoform, CD45RO, but not the longest isoform, CD45RA. Here, we showed that IL-6 induced the translocation of CD45 to lipid rafts in an isoform-dependent manner. In myeloma cells, CD45RO was translocated to lipid rafts more rapidly than CD45RB, but exogenously expressed CD45RA was not translocated. When an IL-6Ralpha-transfected B-cell line was stimulated with IL-6, CD45RA was not translocated, although CD45RB was. We further confirmed that the translocated CD45 bound to IL-6Ralpha, Lyn, and flotillin-2, and this was followed by the dephosphorylation of the negative regulatory Tyr507 of Lyn. CD45 also bound to phosphoprotein associated with glycosphingolipid-enriched microdomains (PAGs), which were subsequently dephosphorylated, resulting in the release of C-terminal src kinase (Csk) from lipid rafts. Therefore, these results indicate that a rapid translocation of CD45RO to lipid rafts may be responsible for IL-6-induced proliferation, and that the change from CD45RA to CD45RO confers the ability to respond to IL-6 in human myeloma cells.
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PMID:A rapid translocation of CD45RO but not CD45RA to lipid rafts in IL-6-induced proliferation in myeloma. 1562 31

The study was aimed at the proper detection of surface and cytoplasmic clonal Ig light/heavy chains in the frame of multiparameter flow cytometry analysis of some B-cell malignancies. An exact direct evidence has been obtained that the leukemia cells following staining by antibodies to immunoglobulins will need to be washed to eliminate free plasma Igs. The results of proper Ig detection with simultaneous unaltered staining of further 2-3 markers on the cell surface after elimination of free plasma Ig in the whole blood sample are described. In differential diagnosis of some chronic B-cell malignancies and subclassification of some acute B-leukemias the detection of intracytoplasmic light/heavy chain Igs is required. The unique phenotypic structures of multiple myeloma (MM) cells have been utilized in our approach to detect cytoplasmic Ig light and heavy chains. A modified 2-step method for analysis of cytoplasmic immunoglobulin light chains by flow cytometry in MM patients was used and the method was extended for measurement of IgM heavy chain in B-ALL. For membrane staining in MM patients cells the combination of CD45-FITC and CD138-PE was used; the CD138 was found to be more specific than CD38 for MM cells. The whole blood cells were lysed, acquired on flow cytometry (first acquisition), then permeabilized by paraformaldehyde and saponin, and incubated with anti-kappa-FITC and anti-lambda-FITC antibodies and acquired again (second acquisition). In B-ALL patients cells in first step the combinations of CD45-FITC or CD22-FITC and CD10-PE have been successfully applied and after RBC lysis, acquisition and membrane permeabilization anti-IgA-FITC and anti-IgM-FITC were applied and cells were acquired again. The FITC fluorescence intensity of the second measurement was equal to the sum of surface CD45 or CD22 marker expression during the first step, and cytoplasmic clonal light or heavy chains expression during the second acquisition in both, MM and pre-B ALL patients, as well.
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PMID:Analysis of surface and cytoplasmic immunoglobulin light/heavy chains by flow cytometry using a lysed-whole-blood technique: Implications for the differential diagnosis of B-cell malignancies. 1564 Sep 50

In this study we quantified the proliferation rate of normal and malignant plasma cells (PCs) by ex vivo incorporation of 5-bromo-2'-deoxyuridine (BrdU; labeling index, LI) using flow cytometry. We show that all bone marrow PCs, either normal or malignant, include a subset of proliferating PCs present within the CD45(bright) fraction. Indeed, medullary normal and malignant PCs were always heterogeneous for CD45 expression, and proliferation was always restricted primarily to the CD45(bright) compartment. Moreover, an inverse correlation was found between LI or CD45 and B-cell lymphoma 2 (Bcl-2) in both malignant and normal PCs, the most proliferating CD45(bright) PCs have the lowest Bcl-2 expression. We investigated expression of molecules of interest in multiple myeloma (MM)-that is, CD138, CD19, CD20, CD27, CD28, CD56, and CD11a-to further characterize the CD45(bright) fraction. Among all of these molecules, only CD11a was exclusively expressed by CD45(bright) proliferating myeloma cells. In conclusion, proliferating myeloma cells are characterized by the specific CD45(bright) CD11a(pos) Bcl-2(low) phenotype.
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PMID:Phenotypic characterization of the human myeloma cell growth fraction. 1574 Dec 17

To develop a method for identification of differential gene expression between different cell populations, several convenient techniques of molecular biology, including subtractive hybridization, suppression PCR, T/A cloning and sequencing, were used to identify genes expressed differentially in CD45+ and CD45- cells isolated from U266 cell line of multiple myeloma. Our results showed that the levels of abundant genes scale down 20 times through subtractive hybridization. Plasmid DNA from CD45- cell clones was hybridized with forward or backward cDNA probes synthesized from CD45- and CD45- cells, respectively. A few of differentially expressed genes reconfirmed by RT-PCR were identified from 500 expressed clones of CD45+ cells. It is concluded that a strategy for gene expression identification developed from conventional molecular biological methods can be used in different laboratories.
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PMID:An integrated technique for identification of differential genes expressed in patients with cancer. 1579 46

We analyzed both morphologic and phenotypic findings of myeloma cells before and after chemotherapy in 21 patients with multiple myeloma. The morphologic analysis was based on the Greipp classification, and phenotypic analysis was performed by 3-color flow cytometry using the CD38 plasma gating method (Marrow plasma 38). Results with flow cytometry using a combination of MPC1, CD49e, and CD45 supported the morphologic findings for the myeloma cells. Treatment with 3 or 4 cycles of VAD (vincristine, doxorubicin, and dexamethasone) therapy was effective in reducing the total numbers of myeloma cells, but the proportion of immature myeloma cells increased after this treatment. However, the immature myeloma cells were reduced by high-dose melphalan (HD-Mel) therapy followed by autologous stem cell transplantation (ASCT). High-dose cyclophosphamide treatment for stem cell harvesting did not show an effect on the residual immature myeloma cells after VAD treatment. In addition, thalidomide was not effective in reducing the numbers of immature myeloma cells. These results suggest that VAD (3 or 4 cycles) therapy plus HD-Mel followed by ASCT is a reasonable treatment for multiple myeloma and that Marrow plasma 38 analysis is a useful method for monitoring the response of multiple myeloma to chemotherapy.
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PMID:The maturation of myeloma cells correlates with sensitivity to chemotherapeutic agents. 1591 66


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