UMLS:C0026764 - FACTA Search

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Query: UMLS:C0026764 (multiple myeloma)
36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deregulated expression of both Myc and Bcl-X(L) are consistent features of human plasma cell neoplasms (PCNs). To investigate whether targeted expression of Myc and Bcl-X(L) in mouse plasma cells might lead to an improved model of human PCN, we generated Myc transgenics by inserting a single-copy histidine-tagged mouse Myc gene, Myc(His), into the mouse Ig heavy-chain Calpha locus. We also generated Bcl-X(L) transgenic mice that contain a multicopy Flag-tagged mouse Bcl-x(Flag) transgene driven by the mouse Ig kappa light-chain 3' enhancer. Single-transgenic Bcl-X(L) mice remained tumor free by 380 days of age, whereas single-transgenic Myc mice developed B cell tumors infrequently (4 of 43, 9.3%). In contrast, double-transgenic Myc/Bcl-X(L) mice developed plasma cell tumors with short onset (135 days on average) and full penetrance (100% tumor incidence). These tumors produced monoclonal Ig, infiltrated the bone marrow, and contained elevated amounts of Myc(His) and Bcl-X(L)(Flag) proteins compared with the plasma cells that accumulated in large numbers in young tumor-free Myc/Bcl-X(L) mice. Our findings demonstrate that the enforced expression of Myc and Bcl-X(L) by Ig enhancers with peak activity in plasma cells generates a mouse model of human PCN that recapitulates some features of human multiple myeloma.
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PMID:Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma cell neoplasms in mice. 1519 11

High-dose therapy with stem cell transplantation (SCT) and novel targeted therapies (thalidomide, its more potent analogues, and bortezomib) represent two approaches for overcoming resistance of multiple myeloma (MM) cells to conventional therapies. While it is now clear that dose-intensification improves the outcome in younger patients, long-term remissions are obtained in a minority of patients. Therefore, the impact of novel agents as part of front-line therapy is the objective of ongoing trials. Gene expression profiling (GEP) will help to improve the management of MM not only by identifying prognostic subgroups but also by defining molecular pathways that are associated with these subgroups and that are possible targets for future therapies. In Section I, Dr. John Shaughnessy describes recent data obtained with GEP of CD138-purified plasma cells from patients with MM. His group has already shown that overexpression of the Wnt signaling inhibitor DKK1 by MM plasma cells blocks osteoblast differentiation and contributes to the development of osteolytic bone lesions. Recent data allow identification of four subgroups of MM in which GEP is highly correlated not only with different clinical characteristics and outcome but also with different cytogenetic abnormalities. In addition, abnormal expression of only three genes (RAN, ZHX-2, CHC1L) is associated with rapid relapses. In the context of intensive therapy with tandem autotransplantations, this model appears to be more powerful than current prognostic models based on standard biologic variables and cytogenetics. Understanding why the dysregulation of these three genes is associated with a more aggressive behavior of the disease will help to define new therapeutic strategies. In Section II, Dr. Jean-Luc Harousseau presents recent results achieved with tandem autologous SCT (ASCT) and with reduced intensity conditioning (RIC) allogeneic SCT. ASCT is now considered as the standard of care in patients up to 65 years of age. The IFM (Intergroupe Francophone du Myelome) has recently shown that double ASCT is superior to single ASCT. Current results of three other randomized trials confirm that double ASCT is superior, at least in terms of event-free survival. However, patients with poor prognostic features do poorly even after tandem ASCT. Strategies to further improve the outcome of ASCT include more intensive therapies and the use of novel agents such as thalidomide and immunomodulatory analogs (IMiDs) or bortezomib. Results of allogeneic SCT remain disappointing in MM even with T cell-depleted grafts. Preliminary results of a strategy combining ASCT to reduce tumor burden and RIC allogeneic SCT are encouraging, although the follow-up is still short. However, again, patients with chromosome 13 deletions have poor results with RIC. Longer follow-up of ongoing multicentric studies will help to clarify the indications of RIC. In Section III, Dr. Paul Richardson summarizes current knowledge of novel targeted therapies in MM. A better understanding of interactions between MM cells and bone marrow stromal cells and of the signaling cascades whereby cytokines mediate proliferation, survival, drug resistance and migration of MM cells provide the rationale for testing novel agents in relapsed/refractory MM. Increased angiogenesis coupled with the known anti-angiogenesis activity of thalidomide justified its use in refractory MM. The remarkable responses initially achieved prompted a number of clinical studies in different indications and the development of more potent IMIDs. Among them CC-5013 (Revlimid) has been tested in Phase I/II studies and a randomized Phase III study has just been completed. Blockade of NF-kappa B using the proteasome inhibitor bortezomib (Velcade) may mediate anti-MM activity by inhibiting interleukin (IL)-6 production in stromal cells and other mechanisms of action have been shown in preclinical studies. Based on the promising results of the Phase II trial, a large randomized trial of bortezomib versus dexamethasone has been completed. Studies of bortezomib combined with other drugs are ongoing. Arsenic trioxide has a number of properties showing that it targets MM cells interacting with the microenvironment. Clinical studies are ongoing as well. Other agents in MM have already been or will probably be translated soon from the bench to the bedside.
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PMID:Multiple myeloma. 1556 86

We have studied the mechanism of apoptosis elicited by the farnesyltransferase inhibitor (R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662) in human myeloma cell lines. Low concentrations of BMS-214662 efficiently inhibited protein farnesylation but did not affect the activation of Akt. BMS-214662 treatment increased levels of the BH3-only protein PUMA; induced proapoptotic conformational changes of Bax and Bak; reduced Mcl-1 levels; caused mitochondrial transmembrane potential loss; induced cytochrome c release, caspase activation, apoptosis-inducing factor (AIF) nuclear translocation, and phosphatidylserine exposure; and allowed the development of apoptotic morphology. Western blot analysis of cell extracts revealed the activation of caspases 2, 3, 8, and 9 upon treatment with BMS-214662. The general caspase inhibitor Z-VAD-fmk significantly prevented BMS-214662-induced death in U266 and RPMI 8226 cells but not in NCI-H929 cells. A mixture of selective caspase inhibitors for caspases 9 [N-benzyloxycarbonyl-Leu-Glu-His-Asp-fluoromethyl ketone (Z-LEHD-fmk)], 3 (Z-DEVD-fmk), and 6 (Z-VEID-fmk) approached the protective effect of Z-VAD upon cell death. However, Z-VAD-fmk did not prevent BMS-214662-induced Bax and Bak activation and decrease of Mcl-1 levels. According to its effect on cell death, Z-VAD-fmk inhibited nuclear translocation of AIF in RPMI 8226 and U266 but not in NCI-H929 cells. These results suggest that apoptosis triggered by BMS-214662 is initiated by a PUMA/Bax/Bak/Mcl-1-dependent mechanism. In some cell lines, Bax/Bak activation is not sufficient per se to induce mitochondrial failure and release of apoptogenic proteins, and so caspases need to be activated to facilitate apoptosis. After DeltaPsi(m) loss, execution of apoptosis was performed in all cases by a cytochrome c-enabled, caspase-9-triggered, caspase cascade and the nuclear action of AIF.
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PMID:Farnesyltransferase inhibitor BMS-214662 induces apoptosis in myeloma cells through PUMA up-regulation, Bax and Bak activation, and Mcl-1 elimination. 1573 11

We encountered two cases of pulmonary infection by Mycobacterium abscessus (M. abscessus). [Case 1] A 66-year-old man who had been treated for non-tuberculous mycobacterium in the past was admitted because of productive cough. His chest X-ray film showed cavitation and direct microscopy of sputum revealed positive acid-fast bacilli (AFB). He was given rifampicin (RFP), ethambutol (EB), and clarythromycin (CAM), and then his symptoms and radiographic findings improved. [Case 2] A 74-year-old man with multiple myeloma as an underlying disease was admitted because of a cavitation found on chest radiography and a positive result for AFB in his sputum. Standard antituberculous drug therapy with isoniazid (INH), RFP, EB, and pyradinamide (PZA) was initiated and then the chest radiographic findings improved. As M. abscessus was isolated two weeks after the induction of therapy, the therapeutic regimen was changed to another combination therapy consisting of EB, clarithromycin (CAM) and ciprofloxacin (CPFX), and then his symptoms and radiographic findings were further improved. In both cases, the bacilli found in their sputum were identified as M. abscessus by DNA hybridization. They were completely resistant to all anti-tuberculosis agents and many antibiotics with a high value of MIC. However, their symptoms, radiographic abnormalities and the results of sputum examination improved following chemotherapy. The results obtained by MIC measurement were inconsistent with the clinical outcomes. The measurement of the MIC value of antibiotics do not necessarily predict its therapeutic effect.
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PMID:[Two cases of pulmonary infection by Mycobacterium abscessus in which drug susceptibility testing results conflicted with clinical courses]. 1596 72

Plasma cell leukemia (PCL) is a rare disease and is the least common variant of multiple myeloma accounting for 2-3% of all plasma cell dyscrasias. We report a patient who presented with history of high grade fever, weakness, palpitations, loss of appetite, bone pains and mental confusion for twenty days. Initial evaluation revealed plasmacytosis with blood plasma cell count of 5184/cumm. His hemoglobin (Hb) was 11.3 gm/dl, platelets were 75000/cumm and total leucocyte count (TLC) was 21600/cumm (24% plasma cells). Bone marrow examination revealed >60% plasmablasts. Serum LDH was high at 3117 U/L and serum calcium was also elevated at 13.9 mg/dl. A diagnosis of PCL was made and the patient was started on treatment for hypercalcaemia with Melphalan/Prednisolone regime along with supportive care. Patient deteriorated very rapidly despite treatment and died on the eighth day. A detailed report of this case and a review of PCL is presented here.
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PMID:Plasma cell leukemia: case report of a rare and aggressive variant of multiple myeloma. 1630 56

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

We describe 2 cases of conventional therapy-resistant multiple myeloma (MM) that responded to bortezomib and dexamethasone therapy. Case 1: A 62-year-old woman with MM (IgG, kappa-type, stage IIIA) resistant to DMVM-IFN (dexamethasone, ranimustine, vincristine, melphalan, interferon-a), VAD (vincristine, doxorubicin, dexamethasone), high-dose melphalan with autologous peripheral blood stem cell transplantation (PBSCT) and thalidomide, received 2 courses of bortezomib treatment. In the first course, bortezomib alone was administered and then in the second course bortezomib was given in combination with dexamethasone. The patient's serum IgG level decreased from 8040 to 1020 mg/dl and the level of plasma cells in bone marrow was 1.2% after the treatments. Adverse reactions including rash, anemia, and thrombocytopenia occurred in the first course; however, they were milder in the second course combined with dexamethasone. Case 2: A 43-year-old man with MM (IgD, gamma-type, stage IIA) resistant to conventional and high-dose chemotherapy with PBSCT as well as thalidomide therapy, received treatment with bortezomib alone and then in combination with dexamethasone. His serum IgD level decreased from 2140 to 623 mg/dl. He suffered adverse reactions such as fatigue, anemia, and thrombocytopenia in the first course, which were relieved in the second course. These results indicate that the combination of bortezomib and dexamethasone is effective in the treatment of refractory MM and that dexamethasone can reduce the adverse reactions of bortezomib.
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PMID:[Effective combination therapy of bortezomib and dexamethasone for two patients with refractory multiple myeloma]. 1644 59

The authors have recently reported that gene-targeted iMyc(Emu) mice that carry a His(6)-tagged mouse Myc cDNA, Myc(His), just 5' of the immunoglobulin heavy-chain enhancer, Emu, are prone to 'spontaneous' neoplasms of the B-lymphocyte lineage. The present study has used histological, immunohistochemical, and molecular genetic methods to investigate a subset of these neoplasms referred to as extraosseous plasmacytomas (PCTs). It is shown that 20.8% (20/96) of tumour-bearing iMyc(Emu) mice on a mixed genetic background of segregating C57BL/6 and 129/SvJ alleles develop PCT by 500 days. The Myc(His)-induced PCTs produced monoclonal immunoglobulin and developed in the gut-associated lymphoid tissue (GALT), particularly the mesenteric node and Peyer's patches. The PCTs overexpressed Myc(His), at the expense of normal Myc, and exhibited gene expression changes on cDNA macroarrays that were consistent with Myc(His)-driven neoplasia. Surprisingly, in one of three PCT-derived cell lines, Myc(His) was 'replaced' by a naturally occurring T(12;15) translocation, which changed the mode of Myc deregulation from gene insertion (Myc(His) transgene) to chromosomal translocation (juxtaposition of normal Myc to the immunoglobulin heavy-chain locus Igh). These findings provide evidence that recreation of the mouse PCT-associated T(12;15)(Igh(Emu)-Myc) translocation by gene insertion in mice results in the predictable development of PCTs in approximately one-fifth of the tumour-bearing mice. Myc(His)-driven PCTs recapitulate aspects of human plasma cell neoplasms, for which relatively few models exist in mice. For example, PCT development in the iMyc(Emu) mice may provide a good system to study the mechanism by which human MYC facilitates the progression of plasma cell myeloma (multiple myeloma) in humans.
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PMID:Plasma cell tumour progression in iMycEmu gene-insertion mice. 1648 95

Characterization of the antigens recognized by tumor-reactive T cells isolated from patients successfully treated with allogeneic HLA-matched hematopoietic stem cell transplantation (SCT) can lead to the identification of clinically relevant target molecules. We isolated tumor-reactive cytotoxic CD8(+) T-cell (CTL) clones from a patient successfully treated with donor lymphocyte infusion for relapsed multiple myeloma after allogeneic HLA-matched SCT. Using cDNA expression cloning, the target molecule of an HLA-B7-restricted CTL clone was identified. The CTL clone recognized a minor histocompatibility antigen produced by a single nucleotide polymorphism (SNP) in the angiogenic endothelial-cell growth factor-1 (ECGF1) gene also known as thymidine phosphorylase. The SNP leads to an Arg-to-His substitution in an alternatively translated peptide that is recognized by the CTL. The ECGF1 gene is predominantly expressed in hematopoietic cells, although low expression can also be detected in other tissues. The patient from whom this CTL clone was isolated had mild graft-versus-host disease despite high numbers of circulating ECGF-1-specific T cells as detected by tetramer staining. Because solid tumors expressing ECGF-1 could also be lysed by the CTL, ECGF-1 is an interesting target for immunotherapy of both hematologic and solid tumors.
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PMID:Identification of the angiogenic endothelial-cell growth factor-1/thymidine phosphorylase as a potential target for immunotherapy of cancer. 1649 72

Anti-calcyclin binding protein (CacyBP) monoclonal antibodies (MAb) were produced using an in vitro immunization method. BALB/c mouse splenocytes were immunized with purified 6 x His-CacyBP fusion protein and fused with myeloma cells using polyethylene glycol (PEG) 4000. By selection using enzyme-linked immunosorbent assay (ELISA), three anti-CacyBP MAbs were obtained. The MAb BD1, whose isotype was IgG1, interacted with the fusion protein. Western blot and immunofluorescence microscopy showed that the MAb BD1 against CacyBP could recognize CacyBP protein derived from human gastric cancer cell lines in both native and denatured forms. This MAb would act as a useful tool for the detection of CacyBP protein in future studies.
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PMID:Establishment and characterization of calcyclin binding protein (CacyBP) monoclonal antibody. 1670 10

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