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)

This study was undertaken to analyze the differentiation profiles assessed by immunophenotyping in AIDS-related B-cell lymphoma (ARL) and their relation to the clinical course. Paraffin-embedded sections of 89 ARL cases during 1989 to 2004 were stained immunohistochemically with antibodies to CD3, CD10, CD20, CD38, CD138/Syndecan-1 (Syn-1), multiple myeloma-1/interferon regulatory factor-4 (MUM1/IRF4), B-cell lymphoma protein-2 (BCL-2), BCL-6, latent membrane protein-1 (LMP-1), and Ki-67. Expression of CD10 and CD20 were associated with better overall survival (OS; P = .009 and P = .04, respectively). Expression of CD20 was associated with longer disease-free survival (DFS; P = .03), whereas expression of CD138/Syn-1 was associated with shorter DFS (P = .03). OS and DFS were worse in patients with immunophenotypic profiles related to post-germinal center (GC) differentiation (BCL-6 and CD10 negative, MUM1/IRF4 and/or CD138/Syn-1 positive) when compared with GC differentiation (P = .01). When controlled for age-adjusted International Prognostic Index (IPI), prior AIDS-defining illness (ADI), and year of ARL diagnosis, a post-GC differentiation remained significantly associated with poor OS and DFS. Expression of CD10 was associated with a preserved immunocompetence, whereas CD20 was less frequent in patients developing ARL while on highly active antiretroviral therapy (P = .04). In summary, lack of CD20 or CD10 expression and a post-germinal center signature are associated with a worse prognosis in ARL.
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PMID:AIDS-related B-cell lymphoma (ARL): correlation of prognosis with differentiation profiles assessed by immunophenotyping. 1590 93

We report the case of a 54-year-old African-American male with IgG multiple myeloma (MM) with disease resistant to multiple chemotherapy regimens and immunomodulatory treatment with thalidomide. In spite of achieving a partial remission of short duration, his disease accelerated to peripheral plasmacytosis and subsequent development of cutaneous plasmacytomas. The malignant plasma cells derived from the dermal lesions were CD45+, CD38+, CD138+ and matched the immunophenotype of the plasmacytes during the leukaemic phase. Occurrence of extramedullary lesions in the setting of MM treated with thalidomide is of concern, although currently there are very few reports describing this association. We discuss the possible relationship between the patient's unusual disease course and the administered chemo- and immunotherapy. The significance of the changes in adhesion molecules, especially CD138 and CD56, relevant to the development of cutaneous plasmacytomas is discussed.
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PMID:Unusual cutaneous involvement during plasma cell leukaemia phase in a multiple myeloma patient after treatment with thalidomide: a case report and review of the literature. 1595 79

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

Defects in the mismatch repair system are associated with a microsatellite unstable phenotype. In this chapter, we describe the preparation of purified plasma cells using CD138 magnetic microbeads as a source of tumor DNA. We also describe a robust, sensitive method for comparing microsatellite repeat units of tumor to constitutive DNA using polymerase chain reaction and laser scanning of fluorescently labeled amplicons in an automated sequencer in order to assess microsatellite instability in myeloma.
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PMID:Detecting mismatch repair defects in myeloma. 1596 10

Monoclonal antibodies (mAb) directed against lineage-specific B-cell antigens have provided clinical benefit for patients with hematologic malignancies, but to date no antibody-mediated immunotherapy is available for multiple myeloma. In the present study, we assessed the efficacy of a fully human anti-CD40 mAb CHIR-12.12 against human multiple myeloma cells. CHIR-12.12, generated in XenoMouse mice, binds to CD138-expressing multiple myeloma lines and freshly purified CD138-expressing cells from >80% multiple myeloma patients, as assessed by flow cytometry. Importantly, CHIR-12.12 abrogates CD40L-induced growth and survival of CD40-expressing patient multiple myeloma cells in the presence or absence of bone marrow stromal cells (BMSC), without altering constitutive multiple myeloma cell proliferation. Immunoblotting analysis specifically showed that PI3-K/AKT, nuclear factor-kappaB (NF-kappaB), and extracellular signal-regulated kinase activation induced by CD40L (5 mug/mL) was inhibited by CHIR-12.12 (5 mug/mL). Because CD40 activation induces multiple myeloma cell adhesion to both fibronectin and BMSCs, we next determined whether CHIR-12.12 inhibits this process. CHIR-12.12 decreased CD40L-induced multiple myeloma cell adhesion to fibronectin and BMSCs, whereas control human IgG1 did not. Adhesion of multiple myeloma cells to BMSCs induces interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion, and treatment of multiple myeloma cells with CD40L further enhanced adhesion-induced cytokine secretion; conversely, CHIR-12.12 blocks CD40L-enhanced IL-6 and VEGF secretion in cocultures of multiple myeloma cells with BMSCs. Finally, CHIR-12.12 triggered lysis of multiple myeloma cells via antibody-dependent cellular cytotoxicity (ADCC) but did not induce ADCC against CD40-negative multiple myeloma cells, confirming specificity against CD40-expressing multiple myeloma cells. These results provide the preclinical rationale for clinical trials of CHIR-12.12 to improve patient outcome in multiple myeloma.
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PMID:Human anti-CD40 antagonist antibody triggers significant antitumor activity against human multiple myeloma. 1599 68

Plasma cell microaggregates detected by CD138 immunohistology were demonstrated in 22% of patients achieving morphologic remission 3 months after high-dose therapy for myeloma. Microaggregates were predictive of earlier disease progression, indicating that immunohistology may represent a useful tool in the assessment of minimal disease in patients after high-dose therapy for myeloma.
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PMID:Bone marrow plasma cell microaggregates detected by immunohistology predict earlier relapse in patients with minimal disease after high-dose therapy for myeloma. 1607 23

Syndecan-1 (CD138) is a heparin sulphate proteoglycan that is over expressed on the surface of both normal and malignant plasma cells and actively shed from the cell surface (soluble syndecan-1). Soluble syndecan-1 has been shown to be an independent prognostic factor in myeloma but its role in prognostic classification requires further investigation. We have retrospectively measured soluble syndecan-1 in 324 presentation samples and 154 plateau phase samples from the UK Medical Research Council Myeloma VIth trial. Log-rank analysis showed that the presentation value of soluble syndecan-1 is a highly significant prognostic factor when assessing survival from entry (chi2=14.92, P<0.0001) and remains an important independent prognostic factor when considered in Cox regression models (P<or=0.02) with known independent factors. The magnitude of fall in soluble syndecan-1 from presentation to plateau also had prognostic value when assessing overall survival from plateau (chi2=3.79, P=0.05). In conclusion, this large study confirms that soluble syndecan-1 level is a powerful independent prognostic factor both at diagnosis and at plateau phase.
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PMID:Soluble syndecan-1 level at diagnosis is an independent prognostic factor in multiple myeloma and the extent of fall from diagnosis to plateau predicts for overall survival. 1609 68

Monoclonal gammopathies are a group of diseases characterised by the proliferation of a single clone of plasma cells that produce a homogeneous monoclonal protein (M protein or myeloma protein) that consist of two heavy polypeptide chains of the same class and subclass and two light polypeptide chains of the same type. Multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are the most common monoclonal gammopathies. Despite advances in systemic and supportive therapies, MM is an incurable hematological malignancy with a median survival of between two and three years. Point mutations in the Ras genes can be detected in a variety of human malignancies, indicating that ras activation represents a widespread oncogenic event. Several studies have analysed the incidence of Ras mutation in MM and MGUS with great differences in their results. To date, the etiopathogenesis of these diseases is still unknown and the relevance of Ras mutation to the clinical and biological behaviour of monoclonal gammopathies remains to be elucidated. In this study, we have analysed K-ras codon 12 and N-ras codon 61 mutations on anti-CD138 sorted bone marrow plasma cell samples of 44 cases of monoclonal gammopathies: 30 MM, 13 MGUS and 1 plasma cell leukaemia, using polymerase chain reaction. No mutations within either codon 12 of K-ras or codon 61 of N-ras have been found in any of the samples. These results indicate that Ras mutations do not play a significant role in the pathogenesis of MM in the Spanish population.
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PMID:RAS mutations are uncommon in multiple myeloma and other monoclonal gammopathies. 1614 19

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

Osteopontin (OPN) is a multifunctional bone matrix glycoprotein that is involved in angiogenesis, cell survival and tumor progression. In this study we show that human myeloma cells directly produce OPN and express its major regulating gene Runx2/Cbfa1. The activity of Runx2/Cbfa1 protein in human myeloma cells has also been demonstrated. Moreover, using small interfering RNA (siRNA) to silent Runx2 in myeloma cells, we suppressed OPN mRNA and protein expression. OPN production in myeloma cells was stimulated by growth factors as IL-6 and IFG-1 and in turn OPN stimulated myeloma cell proliferation. In an 'in vitro' angiogenesis system we showed that OPN production by myeloma cells is critical for the proangiogenic effect of myeloma cells. The expression of OPN by purified bone marrow (BM) CD138(+) cells has also been investigated in 60 newly diagnosed multiple myeloma (MM) patients, finding that 40% of MM patients tested expressed OPN. Higher OPN levels have been detected in the BM plasma of MM patients positive for OPN as compared to controls. Moreover, significantly higher BM angiogenesis has been observed in MM patients positive for OPN as compared to those negative. Our data highlight that human myeloma cells with active Runx2/Cbfa1 protein directly produce OPN that is involved in the pathophysiology of MM-induced angiogenesis.
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PMID:Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients. 1620 9


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