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)

Chemokines are a family of 8-10 kDa proteins with a wide range of biological activities including the regulation of leukocyte trafficking, modulation of haemopoietic cell proliferation and adhesion to extracellular matrix molecules. Using a panel of chemokine receptor-specific monoclonal antibodies (MoAb) in a multicolour flow cytometry approach we analysed the expression of the lymphocyte-associated chemokine receptors CXCR4, CXCR5, CCR5 and CCR6 in B cell acute lymphoblastic leukaemia (precursor B-ALL; six cases), B cell chronic lymphocytic leukaemia (B-CLL; 31 cases), multiple myeloma (10 cases), mantle cell lymphoma (MCL, four cases), follicular lymphoma (FL, three cases) and hairy cell leukaemia (HCL, five cases). We demonstrate that CXCR4, CXCR5 and CCR6 are differentially expressed in these B lymphoproliferative disorders depending on the maturational stage of the malignant B cell population investigated. In particular, we found that CXCR4 is strongly expressed on immature ALL blasts whereas no surface immunoreactivity for CXCR5, CCR5 and CCR6 was observed. By contrast, non-Hodgkin's lymphomas (NHLs) corresponding to more mature peripheral B cell subsets (ie B-CLL and MCL) exhibited high expression levels of CXCR4 and CXCR5. Analysis of terminally differentiated myeloma cells revealed a down-regulation of CXCR4, CXCR5 and CCR6. CCR5, which is not expressed in normal B cells, was also absent from the majority of NHLs. However, CCR5 staining was seen in three of five cases of HCL, representing the first example of cross-lineage aberrant chemokine receptor expression in malignant haemopoietic cells.
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PMID:Differential expression of chemokine receptors in B cell malignancies. 1136 35

Multiple myeloma (MM) is a B cell tumor characterized by its selective localization in the bone marrow. The mechanisms that contribute to the multiple myeloma cell recruitment to the bone marrow microenvironment are not well understood. Chemokines play a central role for lymphocyte trafficking and homing. In this study we have investigated expression and functional importance of chemokine receptors in MM-derived cell lines and primary MM cells. We found that MM cell lines express functional CCR1, CXCR3 and CXCR4 receptors, and some also CCR6. Although only a minority of the cell lines responded by calcium mobilization after agonist stimulation, a migratory response to the CCR1 ligands RANTES and MIP-1 alpha was obtained in 5/6 and 4/6, respectively, of the cell lines tested. Five out of six cell lines showed a response to the CXCR4 ligand SDF-1. In addition, 3/6 cell lines migrated in response to MIP-3 alpha and IP-10, ligands for CCR6 and CXCR3, respectively. The expression of CXCR4 and CCR1 and the migration to their ligands, SDF-1, and RANTES and MIP-1 alpha, respectively, were also demonstrated in primary MM cells. These findings suggest that chemokine receptor expression and the migratory capacity of MM cells to their ligands are relevant for the compartmentalization of MM cells in the bone marrow.
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PMID:Expression and function of chemokine receptors in human multiple myeloma. 1252 79

The restricted bone marrow (BM) localisation of multiple myeloma (MM) cells most likely results from a specific homing influenced by chemotactic factors, combined with the proper signals for growth and survival provided by the BM microenvironment. In analogy to the migration and homing of normal lymphocytes, one can hypothesise that the BM homing of MM cells is mediated by a multistep process, involving the concerted action of adhesion molecules and chemokines. In this study, we report that primary MM cells and myeloma derived cell lines (Karpas, LP-1 and MM5.1) express the chemokine receptor CCR2. In addition, we found that the monocyte chemotactic proteins (MCPs) MCP-1, -2 and -3, three chemokines acting as prominent ligands for CCR2, are produced by stromal cells, cultured from normal and MM BM samples. Conditioned medium (CM) from BM stromal cells, as well as MCP-1, -2 and -3, act as chemoattractants for human MM cells. Moreover, a blocking antibody against CCR2, as well as a combination of neutralizing antibodies against MCP-1, -2 and -3, significantly reduced the migration of human MM cells to BM stromal cell CM. The results obtained in this study indicate the involvement of CCR2 and the MCPs in the BM homing of human MM cells.
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PMID:Chemokine receptor CCR2 is expressed by human multiple myeloma cells and mediates migration to bone marrow stromal cell-produced monocyte chemotactic proteins MCP-1, -2 and -3. 1264 22

We report the case of a 59-year-old woman with Durie-Salmon stage IIIB IgGkappa multiple myeloma (MM), who presented 83 days after autologous hematopoietic stem cell transplant (HSCT) with multiple subcutaneous plasmacytomas. These lesions were confined exclusively to sites where the patient had sustained local trauma. The patient had no pre-transplant history of extramedullary disease and no evidence of plasma cells in the peripheral blood at any time throughout the course of her disease. This case represents the first report of refractory MM presenting as multiple subcutaneous plasmacytomas with specific tropism to sites of previous trauma. Selection of tumor cell subclones with unique chemokine receptor expression profiles that may explain this clinical observation is discussed.
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PMID:Subcutaneous plasmacytomas with tropism to sites of previous trauma in a multiple myeloma patient treated with an autologous bone marrow transplant. 1266 40

B cell neoplasms present heterogeneous patterns of lymphoid organ involvement, which may be a result of the differential expression of chemokine receptors. We found that chemokine receptor (CCR)7, CXC chemokine receptor (CXCR)4, or CXCR5, the main chemokine receptors that mediate B cell entry into secondary lymphoid tissues and their homing to T cell and B cell zones therein, were highly expressed in B malignancies with widespread involvement of lymph nodes. Conversely, those pathologies with little or no nodular dissemination showed no expression to very low levels of CCR7 and CXCR5 and low to moderate levels of CXCR4. These findings provide evidence for the role of CCR7, CXCR4, and CXCR5 in determining the pattern of lymphoid organ involvement of B tumors. Functional studies were performed on B malignancies expressing different levels of CCR7, CXCR5, and CXCR4. Multiple myeloma (MM) cells did not express CCR7 nor CXCR5 and did not migrate in response to their ligands; a moderate expression of CXCR4 on MM cells was accompanied by a migratory response to its ligand, CXCL12. By contrast, cells from B cell chronic lymphocytic leukemia (B-CLL) expressed the highest levels of these chemokine receptors and efficiently migrated in response to all ligands of CCR7, CXCR4, and CXCR5. In addition, the migration index of B-CLL cells in response to both of the CCR7 ligands correlated with the presence of clinical lymphadenopathy, thus indicating that the high expression of functional chemokine receptors justifies the widespread character of B-CLL, representing a clinical target for the control of tumor cell dissemination.
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PMID:Chemokine receptors that mediate B cell homing to secondary lymphoid tissues are highly expressed in B cell chronic lymphocytic leukemia and non-Hodgkin lymphomas with widespread nodular dissemination. 1515 73

Plerixafor [Mozobil, AMD 3100, JM 3100, SDZ SID 791] is a bicyclam derivative that acts as a stem cell mobiliser by blocking the CXCR4 chemokine receptor. Plerixafor was synthesised by Johnson Matthey (AnorMED) in collaboration with the Rega Institute of Leuven, Belgium. Plerixafor is in phase III clinical trials in stem cell transplantation among cancer patients. Plerixafor blocks CXCR4, which triggers the rapid movement of stem cells out of the bone marrow and into circulating blood. These cells can then be collected and used in stem cell transplant procedures. Plerixafor had been available for partnering in Europe. However, decisions concerning partnering arrangements were deferred by AnorMED until top-line clinical data became available (expected in 2007). In November 2006, Genzyme Corporation completed its acquisition of AnorMED. Genzyme intends to commercialise plerixafor in >50 countries throughout the world using its existing transplant business. Evotec OAI was selected by AnorMED to support it in the chemical development of plerixafor. Evotec OAI will use EVOdevelop, its integrated chemical and pharmaceutical development platform, to complete the full validation of the process to plerixafor, including process research and development, cGMP manufacturing and analytical work. Evotec OAI will also be responsible for producing the relevant Chemical Manufacturing Control (CMC) documentation for regulatory filings. Top line results from the phase III studies are expected in the second quarter of 2007 and, assuming these are successful, the marketing submissions are planned for the US in 2007 (launch in 2008), and for Canada and Europe in 2008. Plerixafor has orphan drug status for stem cell transplantation in cancer patients in the US and the EU. AnorMED (now Genzyme) decided to pursue a full Marketing Authorisation Application (MAA) in Europe for plerixafor in stem cell transplant. Previously, the company had been planning on filing a CMA (Conditional Marketing Authorisation) in this region. The change in strategy requires additional phase II trials in the five major EU markets. Multicentre phase II trials with plerixafor have begun in Canada and Germany in approximately 50 patients with non-Hodgkin's lymphoma and multiple myeloma (studies EU21 and C201). Enrolment has been completed in a US-based, multicentre, phase II trial (study 2105) of plerixafor plus G-CSF in patients with multiple myeloma and non-Hodgkin's lymphoma. This study is designed to optimise the administration schedule of this combination therapy regimen. Plerixafor has completed a phase II study (study 2104) in multiple myeloma and NHL patients in combination with chemotherapy. A US-based phase II pilot study (study 2108) with plerixafor as a single mobilising agent in multiple myeloma patients undergoing stem cell transplant is underway. Another US-based phase II pilot study (study 2106) is evaluating plerixafor in combination with the standard mobilisation regimen, G-CSF, in patients with Hodgkin's disease undergoing stem cell transplant. AnorMED completed a phase II study (study 2101) evaluating the potential of plerixafor in combination with G-CSF as a therapy for stem cell transplantation compared to G-CSF therapy alone. The study involved patients with multiple myeloma and patients with NHL. Results indicated that the combination regimen was significantly superior to G-CSF treatment alone in stem cell mobilisation. Further trials are planned for plerixafor, to expand its use in transplant and in other indications including one to investigate the potential of plerixafor to improve the effectiveness of chemotherapy in patients with leukaemia. Phase I trials have been completed.
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PMID:Plerixafor: AMD 3100, AMD3100, JM 3100, SDZ SID 791. 1732 9

Multiple myeloma is characterized by extensive bone destruction with little or no new bone formation. A multiplicity of factors including receptor activator NF-kappaB (RANKL), macrophage inflammatory protein-1alpha, interleukin-3 and interleukin-6 can induce osteoclast formation in myeloma and drive the bone destructive process. Furthermore, factors are also produced either in the microenvironment or by myeloma cells themselves, which inhibit osteoblast differentiation and new bone formation. The combination of increased osteoclast formation with little or no bone repair in response to the previous bone destruction explains the severity of the bone disease in myeloma. Studies of the pathophysiology of myeloma bone disease have identified several novel therapeutic targets. These include antibodies to RANKL, chemokine receptor antagonists, which block the effects of chemokines on osteoclast differentiation and proteasome antagonists, which can affect both RANKL production and osteoprotegerin levels as well as inhibit osteoclast and enhance osteoblast differentiation. In addition, many of the new biologic agents being used for the treatment of patients with myeloma also further inhibit the bone destructive process. New therapies that can target both the tumor as well as the severe bone disease should be on the horizon to treat this devastating complication of myeloma.
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PMID:Treatment strategies for bone disease. 1768 18

Chemokines and their receptors play a pivotal role in the regulation of B-lymphocyte trafficking. This study was aimed at investigating the pattern of chemokine receptor expression, including CCR1 to CCR3, CCR5 to CCR7, CXCR1 to CXCR5, and the migration ability of multiple myeloma (MM) plasma cells (PC). PC were recovered from the bone marrow (BM) of 29 MM patients, extramedullary sites of 10 patients and the BM of five controls. Flow cytometry analysis showed that the receptors mainly expressed on malignant BM PC were represented by CXCR4 (70% of patients), CCR1 (25%), CCR2 (25%), CCR5 (17%) and CXCR3 (20%), while other receptors were commonly lacking. The analysis performed on extramedullary (peripheral blood and pleural effusion) malignant PC demonstrated that the most represented receptors were CXCR4 (100%), CCR2 (66%) and CXCR1 (60%). The migratory capability of malignant PC at resting conditions identified three groups of patients with different migration (low, intermediate and high). As CXCR4 was the relevant chemokine receptor expressed by MM PC, its ligand CXCL12 induced their migration. These data suggest that malignant PC from MM display different chemokine receptor profiles and that CXCR4 is fully functional and might play a role in the spreading of the disease.
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PMID:Multiple myeloma plasma cells show different chemokine receptor profiles at sites of disease activity. 1768 53

The interaction between osteoclasts (OCs) and multiple myeloma (MM) cells plays a key role in the pathogenesis of MM-related osteolytic bone disease (OBD). MM cells promote OC formation and, in turn, OCs enhance MM cell proliferation. Chemokines are mediators of MM effects on bone and vice versa; in particular, CCL3 enhances OC formation and promotes MM cell migration and survival. Here, we characterize the effects of MLN3897, a novel specific antagonist of the chemokine receptor CCR1, on both OC formation and OC-MM cell interactions. MLN3897 demonstrates significant impairment of OC formation (by 40%) and function (by 70%), associated with decreased precursor cell multinucleation and down-regulation of c-fos signaling. OCs secrete high levels of CCL3, which triggers MM cell migration; conversely, MLN3897 abrogates its effects by inhibiting Akt signaling. Moreover, MM cell-to-OC adhesion was abrogated by MLN3897, thereby inhibiting MM cell survival and proliferation. Our results therefore show novel biologic sequelae of CCL3 and its inhibition in both osteoclastogenesis and MM cell growth, providing the preclinical rationale for clinical trials of MLN3897 to treat OBD in MM.
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PMID:MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. 1771 91

Multiple myeloma (MM) is a malignant B-cell disorder characterized by a monoclonal expansion of plasma cells (PC) in the bone marrow (BM). During the main course of disease evolution, MM cells depend on the BM microenvironment for their growth and survival. Reciprocal interactions between MM cells and the BM mediate not only MM cell growth, but also protect them against apoptosis and cause bone disease and angiogenesis. A striking feature of MM represents the predominant localization and retention of MM cells in the BM. Although BM PC indeed represent the main neoplastic cell type, small numbers of MM cells can also be detected in the peripheral blood circulation. It can be assumed that these circulating cells represent the tumour-spreading component of the disease. This implicates that MM cells have the capacity to (re)circulate, to extravasate and to migrate to the BM (homing). In analogy to the migration and homing of normal leucocytes, the BM homing of MM cells is mediated by a multistep process of extravasation with adhesion to the endothelium, invasion of the subendothelial basement membrane, followed by further migration within the stroma, mediated by chemotactic factors. At the end stage of disease, MM cells are thought to develop autocrine growth supporting loops that enable them to survive and proliferate in the absence of the BM microenvironment and to become stroma-independent. In this stage, the number of circulating cells increases and growth at extramedullary sites can occur, associated with alteration in adhesion molecule and chemokine receptor expression. This review summarizes the recent progress in the study of the extravasation and homing mechanisms of MM cells.
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PMID:Extravasation and homing mechanisms in multiple myeloma. 1795 14


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