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)

The inability of the immune system to recognize and kill malignant plasma cells in patients with multiple myeloma (MM) has been attributed in part to the ineffective activation of natural killer (NK) cells. In order to activate and target NK cells to the malignant cells in MM we designed a novel recombinant bispecific protein (ULBP2-BB4). While ULBP2 binds the activating NK receptor NKG2D, the BB4 moiety binds to CD138, which is overexpressed on a variety of malignancies, including MM. ULBP2-BB4 strongly activated primary NK cells as demonstrated by a significant increase in interferon-gamma (IFN-gamma) secretion. In vitro, ULBP2-BB4 enhanced the NK-mediated lysis of 2 CD138+ human MM cell lines, U-266 and RPMI-8226, and of primary malignant plasma cells in the allogenic and autologous setting. Moreover, in a nude mouse model with subcutaneously growing RPMI-8226 cells, the cotherapy with ULBP-BB4 and human peripheral blood lymphocytes abrogated the tumor growth. These data suggest potential clinical use of this novel construct in patients with MM. The use of recombinant NK receptor ligands that target NK cells to tumor cells might offer new approaches for other malignancies provided a tumor antigen-specific antibody is available.
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PMID:A novel bispecific protein (ULBP2-BB4) targeting the NKG2D receptor on natural killer (NK) cells and CD138 activates NK cells and has potent antitumor activity against human multiple myeloma in vitro and in vivo. 1621 Mar 38

Multiple myeloma (MM) is a malignancy of differentiated B lymphocytes and has remained an incurable disease. Chromosomal abnormalities are among the most important prognostic parameters for MM. Cytoplasm immunoglobulin-enhanced interphase fluorescent in situ hybridization (FISH) has been a standard cell-targeting method for identifying genomic aberrations in MM. We have developed another cell-targeting approach by using CD138 magnetic microbeads to sort plasma cells for FISH analysis. The FISH panel consisted of four probes targeting RB-1, D13S319, immunoglobulin H, and p53 loci. We reviewed the FISH and conventional cytogenetic results of 60 patients with MM. The present cell-targeting approach in conjunction with the FISH probe panel was more sensitive than FISH performed on untargeted cells in detecting prognostically significant genomic aberrations (72 versus 24%, P = 0.0016). The frequencies of genomic abnormalities identified were similar to previously reported data obtained with the standard cell-targeting method. Therefore, our cell-targeting approach and FISH panel reliably detect prognostically important genomic abnormalities in MM and are potentially suitable for widespread use.
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PMID:A practical approach to the detection of prognostically significant genomic aberrations in multiple myeloma. 1625 53

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

Chronic idiopathic myelofibrosis (CIMF) is a chronic myeloproliferative disorder (CMPD) with progressive fibrosis and extramedullary hematopoiesis. Similar to other CMPDs, the stem cell in CIMF has the potential to differentiate into myeloid or lymphoid lineages, and thus CIMF can culminate in acute leukemia of myeloid or, rarely, lymphoid lineage. We describe an unusual case of CIMF terminating in extramedullary anaplastic plasmacytoma. The patient was a 61-year-old male with an 11-year history of CIMF. His course was complicated by rapidly growing abdominal and inguinal lymphadenopathy. Lymph node biopsy revealed a diffuse undifferentiated infiltrate in the background of extramedullary hematopoiesis. Flow cytometric and immunohistochemical analysis demonstrated plasma cell-related antigens (CD138, CD38, cytoplasmic kappa light chain), epithelial membrane antigen and CD43 in the tumor cells. The myeloid, B-cell or T-cell markers were negative. A clonal immunoglobulin heavy chain gene rearrangement was identified by polymerase chain reaction. The plasma cell origin was further confirmed by electron microscopic examination, which revealed stacks of rough endoplasmic reticulum. Monoclonal gammopathy may occur in CIMF, and rare cases of simultaneous plasma cell myeloma and CIMF have been reported in the literature. However, to the best of our knowledge, this is the first report of CIMF terminating in extramedullary anaplastic plasmacytoma.
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PMID:Chronic idiopathic myelofibrosis terminating in extramedullary anaplastic plasmacytoma. 1632 64

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

SGN-40, a humanized immoglobulin G1 (IgG1) anti-CD40 monoclonal antibody, mediates cytotoxicity against human multiple myeloma (MM) cells via suppression of interleukin (IL)-6-induced proliferative and antiapoptotic effects as well as antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we studied the clinical significance of an immunomodulatory drug lenalidomide on SGN-40-induced cytotoxicity against CD138(+)CD40(+) MM lines and patient MM cells. Pretreatment with lenalidomide sensitized MM cells to SGN-40-induced cell death. Combined lenalidomide and SGN-40 significantly induced MM apoptosis, evidenced by enhanced cleavage of caspase-3/8/poly(ADP-ribose)polymerase and increased sub-G(0) cells, compared with either single agent at the same doses. Pretreatment of effector cells with lenalidomide augmented SGN-40-induced MM cell lysis, associated with an increased number of CD56(+)CD3(-) natural killer (NK) cells expressing CD16 and LFA-1. Importantly, pretreatment with lenalidomide or lenalidomide and SGN-40 markedly enhanced NK-cell-mediated lysis of autologous patient MM cells triggered by SGN-40. Lenalidomide also up-regulated CD40L on CD56(+)CD3(-) NK cells, facilitating IL-2-mediated activation of NK cells. In addition, lenalidomide induced the CD56(dim) NK subset, which are more potent mediators of ADCC against target MM cells than the CD56(bright) NK subset. Finally, pretreatment of both effector and target MM cells with lenalidomide markedly enhanced SGN-40-mediated ADCC against CD40-expressing MM cells. These studies, therefore, show that the addition of lenalidomide to SGN-40 enhances cytotoxicity against MM cells, providing the framework for combined lenalidomide and SGN-40 in a new treatment paradigm to both target MM cells directly and induce immune effectors against MM.
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PMID:Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. 1635 83

Current monoclonal antibody therapies for multiple myeloma have had limited success, perhaps due to narrow target specificity. We have previously described the ability of polyclonal rabbit antithymocyte globulin (rATG) to induce caspase- and cathepsin-mediated apoptosis in human B and plasma cells. We now extend this observation to myeloma cells. Complement independent cell death was measured after addition of rATG (1-1000 microg/mL) to cultures of myeloma cell lines or primary CD138+ isolates from patient bone marrow aspirates. rATG induced significant levels of apoptosis in myeloma cells as assayed by caspase induction, annexin V binding, subdiploid DNA fragmentation, plasma-membrane permeability, and loss of mitochondrial-membrane potential. Addition of complement greatly augmented myeloma-cell death. Binding of rATG to individual myeloma cell-surface proteins, primarily CD38, CD52, CD126, and CD138, was demonstrated by competitive inhibition experiments with targeted monoclonal antibodies. Three pathways of cell death were identified involving caspase activation, cathepsin D, and the genistein sensitive tyrosine kinase pathway. Fab'2 fragments of rATG had reduced proapoptotic activity, which was restored by coincubation with Fc fragments, and anti-CD32 or anti-CD64 antibodies. We conclude that rATG is an effective agent for in vitro induction of apoptosis in multiple myeloma, and that exploratory clinical trials may be warranted.
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PMID:Apoptosis and complement-mediated lysis of myeloma cells by polyclonal rabbit antithymocyte globulin. 1636 90

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

Report is summary of the results of study designed to ascertain the significance of soluble CD138 (sCD138) assessment in patients with different monoclonal gammopathies. Previous studies have shown that sCD138 is shed from the surface of myeloma cells into serum and that this marker is a new independent prognostic parameter in multiple myeloma. In presented study was evaluated serum sCD138 level in 14 patients with monoclonal gammopathy of undetermined significance (MGUS) and in 17 patients with multiple myeloma (MM), all MM patients were treated by high-dose chemotherapy regimen with subsequent autologous transplantation of peripheral blood stem cells. To determine the sCD138 level we used a rapid and simple ELISA procedure. The mean serum sCD138 level of patients with MGUS was 32 ng/ml (range: 5-128). Soluble CD138 levels were elevated in the sera of 10 out of 17 (59%) multiple myeloma patients, the mean baseline sCD138 concentration was 1542 ng/ml (range: 10-17300). In spite of small number of patients the difference between MGUS and MM group was highly statistically significant (p<0.001). Multiple myeloma patients with high level of sCD138 at diagnosis (cut-off value: 500 ng/ml) had worse prognosis despite of good response to chemotherapy in some of them (p=0.029). It seems that determination of sCD138 can be recommended as a helpful and reliable marker for differential diagnosis as well as prognosis of monoclonal gammopathies.
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PMID:The significance of soluble CD138 in diagnosis of monoclonal gammopathies. 1641 9

Pax5 is a transcription factor that is critical in the bone marrow for differentiation and proliferation of B cells until the plasma cell stage. In Pax5(-/-) mice, B-cell development stalls at the pro-B-cell stage. Messenger RNA profiles of alternatively spliced isoforms of Pax5 in bone marrow frequently differ between multiple myeloma (MM) patients and healthy donors. We sought to determine if Pax5 mRNA profiles also differed in blood and unexpectedly detected the presence of a previously unreported exon that alters the amino acid code for the transactivating domain of Pax5 in CD138(-) B cells. This unique exon escapes detection by conventional analyses of RT-PCR products and may serve as a prototype for other exons, in other genes, that escape RT-PCR detection. Eight percent of tested human subjects were heterozygous for an allele with a nonsynonymous nucleotide substitution in the new exon, and one MM patient was homozygotic for this base difference. Subsequent analysis of plasma and B-cell populations from bone marrow revealed a markedly reduced mRNA expression of the new isoform in cells from MM patients when compared to cells from normal subjects.
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PMID:Expression of mRNA for a newly identified Pax5 exon is reduced in multiple myeloma. 1651 92


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