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)

Although Wilm's Tuomor gene (WT1) was first identified as a tumor suppressor gene for Wilm's tumor, WT1 overexpression has been detected in different malignant cell types including leukemia. Increased expression of WT1 in acute leukemia is potentially used as a marker of minimal residual disease. However, the significance of the gene for multiple myeloma is still not clear. To determine the clinical relevance of WT1 expression in multiple myeloma, we examined the association of clinical parameters and WT1 expression in bone marrow for 17 newly diagnosed multiple myeloma patients. WT1 was assessed by real-time quantitative polymerase chain reaction (RQ-PCR) and calculated standardized WT1 expression level per 100 plasma cells in the bone marrow specimen as "corrected WT1". The expression of standardized WT1 and corrected WT1 in myeloma was 59 to 1,600 copies/microg RNA and 0.05 to 406.3 copies/microg RNA/100 plasma cells, respectively, lower than in leukemia. WT1 transcripts increased when clinical factors worsen, including the stage, amount of M protein, Hb, platelet count, blood urea nitrogen (BUN), creatinine, serum alkaline phosphatase (ALP), calcium, beta2-microglobulin, thymidine kinase activity (TK), and C-reactive protein (CRP). In conclusion, the expression level of WT1 could be an additional marker to the standard parameters considered in risk assessment for multiple myeloma.
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PMID:WT1 expression level and clinical factors in multiple myeloma. 1647 22

Wilms' tumor gene (WT1) possesses oncogenic functions and is expressed in various kinds of malignancies, which suggests that the gene's product, the WT1 protein, should be one of the most promising cancer antigens. In fact, the WT1 protein was shown to be highly immunogenic in cancer patients. WT1 peptides that could induce WT1-specific CTLs (WT1 CTL peptides) were identified, and vaccination of cancer patients with these WT1 CTL peptides induced immunological responses, which were assessed by ex vivo immuno-monitoring, such as the tetramer assay, and in vivo immuno-monitoring, such as the peptide-specific delayed type hypersensitivity reaction. The induced immunological responses then led to clinical responses such as solid tumor shrinkage, a decrease in leukemia cells, and reduction of M-protein (multiple myeloma). Long-term stabilization of disease with good quality of life, which might be characteristic of cancer vaccine therapy, was also reported. It is noteworthy that injection with a "single" kind of WT1 peptide elicited an immunological response strong enough to induce a clinical response, indicating that the WT1 peptide vaccine has therapeutic potential. The number of reports of the successful treatment of cancer patients (not only adult but also childhood malignancies) with WT1 vaccination is increasing. Strategies for further improvement in the efficacy of therapy, including combined use of chemotherapy drugs, molecular-target-based drugs, or WT1 helper peptides, are being proposed. WT1 peptide vaccination in an "adjuvant setting" should be considered a promising treatment to protect against progression or relapse of malignancies in cases with minimal residual disease.
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PMID:WT1 peptide vaccine as a paradigm for "cancer antigen-derived peptide"-based immunotherapy for malignancies: successful induction of anti-cancer effect by vaccination with a single kind of WT1 peptide. 1953 72

Monitoring patients with multiple myeloma during and after treatment for the presence of residual myeloma cells (minimal residual disease - MRD) has been shown to give a major insight into the effectiveness of treatment. It has been reported that Wilms' tumor gene (WT1) expression levels measured by real-time quantitative polymerase chain reaction was useful as an indicator of minimal residual disease in leukemia and myelodysplastic syndrome. The aim of this study was to measure levels of WT1 expression, in order to find a possible association between the expression of this gene and multiple myeloma at diagnosis. If an association was found, the WT1 gene could be evaluated as an MRD marker by comparison with other prognostic factors. We investigated peripheral blood WT1 expression level measured by real-time light cycler quantitative polymerase chain reaction in 50 newly diagnosed multiple myeloma patients. The normal WT1 gene copy number was found to be <23/microl cDNA and all patients with myeloma were found to have normal WT1-mRNA levels. On this basis WT1 expression analyses is unlikely to be a useful genetic marker for routine clinical use in multiple myeloma patients at diagnosis.
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PMID:Expression of WT1 gene in multiple myeloma patients at diagnosis: is WT1 gene expression a useful marker in multiple myeloma? 2013 61

T cells with specificity for antigens derived from Wilms Tumor gene (WT1), Proteinase3 (Pr3), and mucin1 (MUC1) have been demonstrated to lyse acute myeloid leukemia (AML) blasts and multiple-myeloma (MM) cells, and strategies to enhance or induce such tumor-specific T cells by vaccination are currently being explored in multiple clinical trials. To test safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted peptides and the pan HLA-DR T helper cell epitope (PADRE) or MUC1-helper epitopes in combination with CpG7909 and MontanideISA51, four patients with AML and five with MM were repetitively vaccinated. No clinical responses were observed. Neither pre-existing nor naive WT1-/Pr3-/MUC1-specific CD8+ T cells expanded in vivo by vaccination. In contrast, a significant decline in vaccine-specific CD8+ T cells was observed. An increase in PADRE-specific CD4+ T helper cells was observed after vaccination but these appeared unable to produce IL2, and CD4+ T cells with a regulatory phenotype increased. Taken into considerations that multiple clinical trials with identical antigens but different adjuvants induced vaccine-specific T cell responses, our data caution that a vaccination with leukemia-associated antigens can be detrimental when combined with MontanideISA51 and CpG7909. Reflecting the time-consuming efforts of clinical trials and the fact that 1/3 of ongoing peptide vaccination trails use CpG and/or Montanide, our data need to be taken into consideration.
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PMID:Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909. 2096 11

The development of T-cell responses specific for myeloma-associated antigens correlates with improved clinical outcomes in multiple myeloma patients undergoing allogeneic T cell-depleted hematopoietic stem cell transplantation and donor lymphocyte infusions. Thus, immunotherapeutic strategies that further increase the frequency of Wilms tumor 1 (WT1)-specific T cells may provide clinical benefits to multiple myeloma patients.
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PMID:The emergence of WT1-specific T-cell responses following allogeneic T cell-depleted hematopoietic stem cell transplantation and low-dose donor lymphocyte infusions is associated with a graft-vs.- myeloma effect. 2407 75

This study was aimed to investigate the expression level of Wilms' tumor 1( WT1) gene in hematologic neoplasm (leukemia, multiple myeloma and lymphoma) patients and its clinical significance. Real-time quantitative polymerase chain reaction (RQ-PCR) was used to detect the copy number of WT1 gene and reference gene (ALB) in bone marrow cells of 228 patients with hematologic neoplasm in our hospital. The gene expression level was determined by using the ratio of the copy number of WT1 gene and reference gene. The results showed that the WT1 expression level between male and female patients was not statistically significantly different (P > 0.05). All the patients were divided into 3 groups: the group aged under 19, the group aged between 19-50, and the group aged over 50; the WT1 expression level among the three groups were not statistically significantly different (P > 0.05) . The above-mentioned patients were redivided into the groups aged under 45 and over 45, the difference between them was not statistically significant (P > 0.05). The difference of WT1 expression level between newly diagnosed patients and treated patients with hematologic neoplasm was statistically significant (P < 0.01), but no statistically significant difference of WT1 expression was found (P > 0.05) at each stage within 3 years after treatment, however, among them the difference between newly diagnosed leukemia patients and treated leukemia patients was very statistically significant (P < 0.01), while the difference between newly diagnosed and treated non-leukemia patients was not statistically significant (P > 0.05). The expression difference of WT1 between leukemia and non-leukemia patients was very statistically significant (P < 0.01), the difference between the newly diagnosed leukemia and non-leukemia patients also was very statistically significant (P < 0.01). The difference of WT1 expression between treated leukemia and non-leukemia patients was not statistically significant (P > 0.05). It is concluded that the WT1 expression level in leukemia patients can be a reliable marker to evaluate the prognosis of newly diagnosed leukemia and the curative effect for minimal residual disease. No WT1 expression difference has been found before and after treatment among the patients with non-leukemia, such as multiple myeloma and lymphoma, therefore, which should be furtherly explored.
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PMID:[WT1 gene expression difference in leukemia and non-leukemia and its clinical significance]. 2533 60

The identification of human Wilms' tumor gene 1 (WT1) protein-derived cytotoxic T lymphocyte (CTL) epitopes and the in vivo efficacy of WT1 peptide-based immunotherapy in a mouse model were reported in 2000. This successful basic research led to clinical studies of a WT1 peptide vaccine, and a positive impact on clinical response was first demonstrated in 2003 in the form of a reduction in blast cells of vaccine-treated patients with myelodysplastic syndromes (MDS). Since then, data on WT1 peptide vaccine-treated patients with immunological and/or clinical response have been accumulated. MDS and acute myeloid leukemia were the major target diseases to provide proof of concept for the therapeutic potential of the WT1 peptide vaccine. WT1 vaccination-induced clinical responses or usefulness were also shown for chronic myeloid leukemia, multiple myeloma, and acute lymphoblastic leukemia, as well as various types of solid cancers. Non-Hodgkin's lymphoma and myeloproliferative neoplasms may also be target diseases because of their WT1 expression. Of note, recent clinical studies have demonstrated that patients with hematological malignancies who have minimal residual disease after chemotherapy or allogeneic hematopoietic stem cell transplantation may be cured by WT1 peptide vaccination. Further enhancement of the efficacy and usefulness of the WT1 peptide vaccine is expected.
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PMID:Wilms' Tumor Gene 1 (WT1) Peptide Vaccine Therapy for Hematological Malignancies: From CTL Epitope Identification to Recent Progress in Clinical Studies Including a Cure-Oriented Strategy. 2904 Oct 12

The functional avidity of T-cell receptor (TCR)-engineered T cells towards their cognate epitope plays a crucial role in successfully targeting and killing tumor cells expressing the tumor-associated antigen (TAA). When evaluating in vitro functional T-cell avidity, an important aspect that is often neglected is the antigen-presenting cell (APC) used in the assay. Cell-based models for antigen-presentation, such as tumor cell lines, represent a valid alternative to autologous APCs due to their availability, off-the-shelf capabilities, and the broad range of possibilities for modification via DNA or messenger RNA (mRNA) transfection. To find a valuable model APC for in vitro validation of TAA Wilms' tumor 1 (WT1)-specific TCRs, we tested four different WT1 peptide-pulsed HLA-A2+ tumor cell lines commonly used in T-cell stimulation assays. We found the multiple myeloma cell line U266 to be a suitable model APC to evaluate differences in mean functional avidity (EC50) values of transgenic TCRs following transfection in 2D3 Jurkat T cells. Next, to assess the dose-dependent antigen-specific responsiveness of WT1 TCR-engineered 2D3 T cells to endogenously processed epitopes, we electroporated U266 cells with different amounts of full-length antigen WT1 mRNA. Finally, we analyzed the functional avidity of WT1 TCR-transfected primary CD8 T cells towards WT1 mRNA-electroporated U266 cells. In this study, we demonstrate that both the APC and the antigen loading method (peptide pulsing versus full-length mRNA transfection) to analyze T-cell functional avidity have a significant impact on the EC50 values of a given TCR. For rapid assessment of the functional avidity of a cloned TCR towards its endogenously processed MHC I-restricted epitope, we showcase that the TAA mRNA-transfected U266 cell line is a suitable and versatile model APC.
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PMID:Rapid Assessment of Functional Avidity of Tumor-Specific T Cell Receptors Using an Antigen-Presenting Tumor Cell Line Electroporated with Full-Length Tumor Antigen mRNA. 3197 92