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

Multiple myeloma (MM) is characterized by accumulation of clonal plasma cells (PCs). CD45, a key regulator of antigen-mediated signaling and activation in lymphocytes, is present in early stages of PCs development. We studied CD45 expression on MM PCs by flow cytometry, correlating it to important biological disease characteristics. Additionally, we examined the expression of various adhesion molecules on PCs. A total of 75 patients with untreated MM (29), relapsed MM (17), smoldering MM (12), and monoclonal gammopathy of undetermined significance (MGUS) (17) were studied. The proportion of PCs expressing CD45 was higher among those with early disease (MGUS or smoldering MM) compared to those with advanced disease (new or relapsed MM) (43 vs 22%; P=0.005). Among those with advanced disease, patients with bone lesions had a lower percentage of CD45-positive (CD45+) PCs; 14 vs 34% (P=0.02). Patients with high-grade angiogenesis had a lower percentage of CD45+ PCs; 13 vs 31% (P=0.03). The median overall survival for the CD45+ group (>20% PCs positive) was 39 vs 18 months for the CD45-negative (CD45-) group (P=0.07). The expression of CD138, CD56 and CD54 were higher among the CD45- PCs. This study demonstrates important biological correlates of CD45 expression on myeloma cells.
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PMID:CD45 expression by bone marrow plasma cells in multiple myeloma: clinical and biological correlations. 1595 33

The aim of our study was to evaluate CD52 as a target molecule for antibody therapy for multiple myeloma. Twenty consecutive bone marrow samples from myeloma patients were studied by flow cytometry using antibodies against CD45, CD38, CD138, CD3, CD19, and CD52. Most myeloma cells did not express CD52; CD52 expression was found only in a small subpopulation of plasma cells with a CD45+CD38++ phenotype. In contrast, the major fraction of myeloma cells (CD45-CD38++) was CD52-. Treatment of myeloma patients with anti-CD52 antibodies with the aim to reduce the number of myeloma cells in the CD45+CD38++ subfraction, which possibly contains a proliferative progenitor cell pool, would be at best a highly experimental approach. We conclude that CD52 is not a promising target for antibody-based therapies for most patients with multiple myeloma.
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PMID:CD52 is not a promising immunotherapy target for most patients with multiple myeloma. 1620 99

Expression of CD45 is quite variable in human myeloma cells and cell lines, such as U266, and CD45(+) U266 proliferates in response to a growth factor, interleukin-6. Here, we show that CD45(+) myeloma cell lines were more sensitive to various apoptotic stimuli, such as oxidative stress and endoplasmic reticulum (ER)-stress, than CD45(-) cells. Reactive oxygen species and calcium ion seemed to be involved in the susceptibility to apoptosis of CD45(+) U266. The activation of the src family kinases associated with CD45 phosphatase played an important role in the augmented apoptosis in CD45(+) U266 by oxidative stress. These results indicate that the CD45-expression renders myeloma cells competent for not only mitogenic but also apoptotic stimuli, resulting in either proliferation or apoptosis of CD45(+) myeloma cells dependently upon the circumstantial stimuli. Furthermore, voltage-dependent anion channel (VDAC) 1 was identified as a gene highly expressed in CD45(+) U266 by cDNA subtraction. The increased expression of VDAC1 seemed to augment the sensitivity to the ER-stress because the VDAC1-transfected U266 was more susceptible to the thapsigargin-induced apoptosis. Thus, CD45 expression accompanied by the increased VDAC1 expression sensitizes myeloma cells to the various extracellular stimuli that trigger apoptosis via the mitochondrial pathways.
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PMID:Increased susceptibility to apoptosis in CD45(+) myeloma cells accompanied by the increased expression of VDAC1. 1624 87

Long-lived plasma cells, residing primarily in the bone marrow, continuously secrete antibody and provide an important component of humoral memory. However, when such cells secrete autoantibodies or become transformed, they can be pathogenic. We have shown recently that the transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp-1) is required for the formation of plasma cells. To determine what role Blimp-1 might play in maintenance of plasma cells, we generated mice in which the gene encoding Blimp-1 could be deleted in an inducible manner. Deletion of Blimp-1 either in vitro or in vivo leads to loss of previously formed B220(LO)CD138(HI) plasma cells. Using BrdU incorporation, we confirmed that Blimp-1 is required for the maintenance of nondividing, long-lived plasma cells in the bone marrow. Blimp-1 is also required for long-term maintenance of antigen-specific immunoglobulin in serum. Thus Blimp-1 is required not only for the formation but also for the maintenance of long-lived plasma cells. This finding provides the possibility of new drug design strategies for autoimmunity and multiple myeloma focused on blocking Blimp-1 expression or activity.
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PMID:Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow. 1631 38

AIDS-associated aggressive B-cell lymphomas often have plasmacytoid features. Plasma cell neoplasms in HIV patients were commonly described to have atypical morphology and an aggressive clinical course in the literature. We reviewed 14 cases of neoplasms with marked plasmacytic differentiation in HIV-positive patients to determine their clinicopathologic features. Of these, 13 of 14 had homogeneous morphology and were generally CD45(+), CD20-, PAX-5-, and CD138(+). All were positive for Epstein-Barr virus-encoded RNA (EBER) but lacked EBV late membrane proteins (LMP). Human herpes virus 8 (HHV8) DNA was detected in 6 of 10 cases by nested PCR, but HHV8 latent nuclear antigen (LNA) was absent. The 13 patients ranged in age from 28 to 44 years (median, 41 years) (11 male patients; 2 female patients). All patients had extramedullary and 11 of 13 had extranodal tumor at the initial presentation; 2 had distant marrow involvement. The most commonly involved location was the oral cavity (6 of 13 cases), followed by bone and soft tissue (4 of 13), and the gastrointestinal tract (3 of 13). All 11 patients with follow-up died within 34 months (median, 7 months). The 14th patient who had a nodal disease with more undifferentiated morphology and expression of the HHV8 LNA protein was alive without disease at last follow-up (>72 months), probably representing a novel HHV8(+) lymphoma. We conclude that most plasmacytic tumors in HIV-positive individuals are extramedullary, clinically aggressive EBV(+) tumors identical to plasmablastic lymphoma that does not have the clinical features of plasma cell myeloma.
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PMID:Plasmablastic lymphoma in HIV-positive patients: an aggressive Epstein-Barr virus-associated extramedullary plasmacytic neoplasm. 1632 36

Detection of circulating myeloma cells (CMCs) by flow cytometry in patients with multiple myeloma (MM) indicates active disease. We hypothesized that detection of CMCs at the time of stem-cell collection prior to autologous stem-cell transplantation (ASCT) identifies patients at high risk of rapid progression. A cohort of patients undergoing ASCT was identified. CMCs were determined by gating on CD38+/CD45- cells using flow cytometry. The impact of CMCs on overall survival (OS) and time to progression (TTP) was evaluated in univariate and multivariate analyses. Of 246 patients undergoing ASCT, 95 had CMCs. Complete response (CR) rates after transplantation were 32% and 36% for patients with and without CMCs, respectively (P = .50). OSs were 33.2 and 58.6 months (P = .01) whereas TTPs were 14.1 and 22 months, respectively (P = .001). On multivariate analysis, CMCs remained independent of cytogenetics and disease status at time of transplantation (P = .03). CMCs and cytogenetics were combined in a new scoring system. Patients with neither, one, or both parameters had a median OS of 55, 48, and 21.5 months and a median TTP of 22, 15.4, and 6.5 months, respectively. CMCs at the time of ASCT is an independent prognostic factor and in combination with cytogenetics provides a powerful scoring system that stratifies patients and guides management.
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PMID:Flow cytometric detection of circulating myeloma cells before transplantation in patients with multiple myeloma: a simple risk stratification system. 1633 99

To establish the method of immunophenotyping testing for patients with multiple myeloma (MM), to analyze the characteristics of antigen expression on myeloma cells, and to purify primary myeloma cells, CD45/side scatter (SSC) gating tri-color immunofluorescence (IF) flow cytometry (FCM) was used to test immunophenotype of 18 patients with MM, 20 patients with acute leukemia (AL) and 7 normal controls. Purified primary myeloma cells were obtained by means of anti-CD138 monoclonal antibody and immunomagnetic microbeads. The results showed that myeloma cells displayed a CD45 negative/low positive expression, and SSC was located between nucleated red blood cells and neutrophils. Both CD138 and CD38 were positive while most antigens of T cell, B cell and myeloid cell were negative. Positive rate of CD56 was 83.3% and HLA-DR was 44.4% positive. Compared with MM patients, CD138 was negative and CD38 was 100% positive in AL patients. CD56 was 25% positive. In normal controls, neither CD138 nor CD56 was positive. The positive rate of primary myeloma cells after purification was 73%-95% with a mean of 86%. It is concluded that CD45/SSC gating procedure is a stable and reliable method to detect immunophenotype of MM. CD138 is a correspondingly special antigen for myeloma cells. Highly enriched primary myeloma cells can be obtained by anti-CD138 antibody and immunomagnetic microbeads.
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PMID:[Significance of CD138/syndecan-1 for multiple myeloma immunophenotypes]. 1640 72

The heterogeneity of bone marrow plasmacytosis is clearly analyzed by multicolor staining with anti-CD38 antibody. To date, at least 5 subpopulations of plasma cells have been identified in the bone marrow of multiple myeloma (MM) patients with regard to the expression of MPC-1, CD49e (VLA-5), and CD45: MPC-1(-)CD49e(-)CD45(+) proliferative immature cells, MPC-1(-)CD49e(-)CD45(-) immature myeloma cells, MPC-1(+)CD49e(-)CD45(-) and MPC-1(+)CD49e(-)CD45(+) intermediate myeloma cells, and MPC-1(+)CD49e(+)CD45(+) mature myeloma cells. We performed phenotypic analyses in 75 cases of monoclonal bone marrow plasmacytosis, including 46 cases of MM and 29 cases of monoclonal gammopathy of undetermined significance (MGUS). In 31 cases of progressive MM disease, MPC-1(-) immature and MPC-1(-)CD45(+) proliferative immature myeloma cells were significantly increased up to >25% and >10%, respectively, of the plasma cell fractions (CD38(++) cells), whereas there were no increases in MPC-1(-) or MPC-1(-)CD45(+) proliferative immature myeloma cells in 15 cases of stable disease. Interestingly, the proportions of MPC-1(-) and MPC-1(-)CD45(+) immature monoclonal plasma cells also increased in the 7 progressive cases of MGUS. Finally, we present the revised (2005) phenotypic classification of monoclonal marrow plasmacytosis (MOMP-2005).
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PMID:An increase in MPC-1- and MPC-1-CD45+ immature myeloma cells in the progressive states of bone marrow plasmacytosis: the revised phenotypic classification of monoclonal marrow plasmacytosis (MOMP-2005). 1644 50

Cellular diversity, which is a hallmark of malignancy, can be generated by both genetic and nongenetic mechanisms. We describe here variability in the adhesive and migratory behavior of malignant plasma cell populations, including multiple myeloma-derived lines and primary patient samples. Examination of the plasma cell lines ARH-77, CAG, and AKR revealed two distinct subpopulations of cells, one displaying highly adhesive properties (type A) and the other consisting of poorly adhesive, floating cells (type F). In the ARH-77 cell line, type A cells attach better to fibronectin and to human bone fragments and form paxillin-rich focal adhesions, whereas type F cells are highly motile and exert integrin-dependent bone marrow homing capacity in nonobese diabetic/severe combined immunodeficient mice. Flow cytometry indicated that type A cells express significantly higher levels of CD45 and CD56 and lower levels of CD138 compared with type F cells. Interestingly, culturing of either type A or type F cells under nonselective conditions resulted in the development of mixed cell population similar to the parental ARH-77 cells. Analysis of bone marrow aspirates of multiple myeloma patients revealed that spicules within the aspirates are enriched with type A-like cells. Nonadherent cells within the aspirate fluids express a marker profile similar to type F cells. This study indicates that multiple myeloma patients contain heterogeneous populations of malignant plasma cells that display distinct properties. Diverse subpopulations of malignant plasma cells may play distinct roles in the different biological and clinical manifestations of plasma cell dyscrasias, including bone dissemination and selective adhesion to bone marrow compartments.
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PMID:The generation and regulation of functional diversity of malignant plasma cells. 1695 Nov 74

Insulin-like growth factor 1 (IGF-1) is a well-known growth factor for myeloma cells. Thus, therapeutic strategies targeting IGF-1R have been proposed for multiple myeloma treatment. In this study, we investigated the effect of the antagonistic anti-IGF-1R murineAVE1642 Ab (mAVE1642). We show that mAVE1642 selectively inhibits IGF-1R but not insulin signaling in human myeloma cell lines. Since we have previously shown the functional relevance of CD45 expression in the growth of myeloma cells and the association of CD45-negative (CD45neg) status with a less favorable clinical outcome, both CD45-positive (CD45pos) and CD45neg myeloma cell lines were selected for our study. We found that mAVE1642 strongly inhibits the growth of CD45neg myeloma cell lines, leading to a G1 growth arrest, whereas it has almost no effect on the growth of CD45pos myeloma cell lines. Furthermore, mAVE1642 binding induced a significant reduction of IGF-1R expression. We next demonstrated that the overexpression of IGF-1R in the CD45pos myeloma cell line increased Akt phosphorylation but was not sufficient to sensitize these cells to mAVE1642. In contrast, we generated a stable CD45-silencing XG-1 cell line and showed that it became sensitive to mAVE1642. Thus, for the first time, we provided direct evidence that the expression of CD45 renders cells resistant to mAVE1642. Taken together, these results support that therapy directed against IGF-1R can be beneficial in treating CD45neg patients.
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PMID:CD45neg but not CD45pos human myeloma cells are sensitive to the inhibition of IGF-1 signaling by a murine anti-IGF-1R monoclonal antibody, mAVE1642. 1695 88


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