Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukemic cells from seventy patients with various types of human leukemias were examined for expression of the WT1 gene, the Wilms' tumor gene located at chromosome 11p13. WT1 was expressed in 7 of 16 cases of acute lymphoblastic leukemia, 15 of 22 with acute myelogenous leukemia and 8 of 10 in blast crisis of chronic myelogenous leukemia. No detectable WT1 RNA was found in chronic leukemias, including chronic lymphocytic leukemia, plasma cell leukemia, hairy cell leukemia and chronic myelogenous leukemia in chronic phase. The expression pattern of WT1 in these human leukemia samples indicates the involvement of this gene in the early stage of hematological cell differentiation.
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PMID:Expression of the Wilms' tumor gene (WT1) in human leukemias. 131 88

Wilms' tumor (WT) is a pediatric malignancy that occurs in embryonic kidney. Recently, a putative Wilms' tumor gene (WT1), located on chromosome 11p13, was isolated and characterized. We found constitutive expression of WT1 mRNA in eight out of 22 hematopoietic cell lines and seven out of 26 clinical samples which were derived from patients with various types of hematologic malignancies. WT1 mRNA was detected in four out of six myeloid cell lines, four out of 10 cases of acute myelocytic leukemia, three out of 15 lymphoid cell lines, one out of nine cases of lymphoid malignancies, and one out of six cases of chronic myelocytic leukemia in accelerated phase and blast crisis. One unclassified hematopoietic cell line and a case of myelodysplastic syndrome also expressed WT1 mRNA. No mutations were detectable in the cell lines by Southern blot analysis and a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis in the four zinc finger domains of the WT1 gene. These results suggest that WT1 gene is expressed in several types of immature lymphoid or myeloid leukemia cells possibly without alterations of the WT1 gene.
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PMID:Expression of the candidate Wilm's tumor gene, WT1, in human leukemia cells. 832 Oct 47

The Wilms' tumor gene WT1 is expressed at high levels not only in acute myelocytic and lymphocytic leukemia and in chronic myelocytic leukemia but also in various types of solid tumors including lung cancers. To determine whether the WT1 protein can serve as a target Ag for tumor-specific immunity, three 9-mer WT1 peptides (Db126, Db221, and Db235), which contain H-2Db-binding anchor motifs and have a comparatively higher binding affinity for H-2Db molecules, were tested in mice (C57BL/6, H-2Db) for in vivo induction of CTLs directed against these WT1 peptides. Only one peptide, Db126, with the highest binding affinity for H-2Db molecules induced vigorous CTL responses. The CTLs specifically lysed not only Db126-pulsed target cells dependently upon Db126 concentrations but also WT1-expressing tumor cells in an H-2Db-restricted manner. The sensitizing activity to the Db126-specific CTLs was recovered from the cell extract of WT1-expressing tumor cells targeted by the CTLs in the same retention time as that needed for the synthetic Db126 peptide in RP-HPLC, indicating that the Db126-specific CTLs recognize the Db126 peptide to kill WT1-expressing target cells. Furthermore, mice immunized with the Db126 peptide rejected challenges by WT1-expressing tumor cells and survived for a long time with no signs of autoaggression by the CTLs. Thus, the WT1 protein was identified as a novel tumor Ag. Immunotherapy targeting the WT1 protein should find clinical application for various types of human cancers.
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PMID:Cancer immunotherapy targeting Wilms' tumor gene WT1 product. 1065 36

The product of the Wilms' tumor gene WT1 is a transcription factor overexpressed not only in leukemic blast cells of almost all patients with acute myeloid leukemia, acute lymphoid leukemia, and chronic myeloid leukemia, but also in various types of solid tumor cells. Thus, it is suggested that the WT1 gene plays an important role in both leukemogenesis and tumorigenesis. Here we tested the potential of WT1 to serve as a target for immunotherapy against leukemia and solid tumors. Four 9-mer WT1 peptides that contain HLA-A2.1-binding anchor motifs were synthesized. Two of them, Db126 and WH187, were determined to bind to HLA-A2.1 molecules in a binding assay using transporter associated with antigen processing-deficient T2 cells. Peripheral blood mononuclear cells from an HLA-A2.1-positive healthy donor were repeatedly sensitized in vitro with T2 cells pulsed with each of these two WT1 peptides, and CD8(+) cytotoxic T lymphocytes (CTLs) that specifically lyse WT1 peptide-pulsed T2 cells in an HLA-A2.1-restricted fashion were induced. The CTLs also exerted specific lysis against WT1-expressing, HLA-A2.1-positive leukemia cells, but not against WT1-expressing, HLA-A2.1-negative leukemia cells, or WT1-nonexpressing, HLA-A2. 1-positive B-lymphoblastoid cells. These data provide the first evidence of human CTL responses specific for the WT1 peptides, and provide a rationale for developing WT1 peptide-based adoptive T-cell therapy and vaccination against leukemia and solid tumors.
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PMID:Human cytotoxic T-lymphocyte responses specific for peptides of the wild-type Wilms' tumor gene (WT1 ) product. 1066 72

Continuous Wilms' tumor gene (WT1) expression is a typical feature of leukemic blasts in AML, ALL, and blast crisis CML patients. It is easily detectable by a variety of RT-PCR protocols, which differ mainly in their sensitivity. The nuclear WT1 protein can be found in blasts of approximately 50-60% of acute leukemia patients at diagnosis. Conversely, WT1 is only transiently expressed in normal hemopoiesis. Early CD34+ hemopoietic progenitors express WT1, whereas no WT1 mRNA transcripts can be found in mature blood cells and differentiation-induced committed CD34- progenitors. As a powerful complementary diagnostic tool, testing for WT1 expression can be helpful to discriminate between eosinophilic leukemia (EoL) patients and patients with idiopathic hypereosinophilic syndromes. Conflicting data about the usefulness of testing for WT1 expression to monitor minimal residual disease (MRD) in treated leukemia patients will be discussed. Finally, research strategies to circumvent shortcomings in detecting leukemia-associated WT1 expression will be outlined.
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PMID:Analysis of Wilms tumor gene (WT1) expression in acute leukemia patients with special reference to the differential diagnosis between eosinophilic leukemia and idiopathic hypereosinophilic syndromes. 1067

Wilms' tumor gene WT1 mRNA is a new marker of leukemic blast cells for AML, ALL, and CML. Minimal residual disease(MRD) of leukemia can be detected at frequencies as low as 1 in 10(3) to 10(4) normal bone marrow cells and 1 in 10(5) normal peripheral blood mononuclear cells by means of the quantitation of WT1 mRNA(WT1 assay) using reverse transcriptase-polymerase chain reaction. Thus, the WT1 assay makes it possible to rapidly assess the effectiveness of treatment and to evaluate the degree of eradication of leukemic cell in individual leukemia patients. Furthermore, WT1 assay can continuously assess the disease progression of myelodysplastic syndromes(MDS) and predict the evolution of MDS to overt AML within 6 months.
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PMID:[Genetic diagnosis of leukemia: diagnosis of relapse and complete remission, and prediction of leukemia onset]. 1080 19

WT1 is an oncogenic protein expressed by the Wilms' tumor gene and overexpressed in the majority of acute myelogenous leukemias (AMLs) and chronic myelogenous leukemias (CMLs). The current study analyzed the sera of patients with AML and CML for the presence of antibodies to full-length and truncated WT1 proteins. Sixteen of 63 patients (25%) with AML had serum antibodies reactive with WT1/full-length protein. Serum antibodies from all 16 were also reactive with WT1/NH2-terminal protein. By marked contrast, only 2 had reactivity to WT1/COOH-terminal protein. Thus, the level of immunological tolerance to the COOH terminus may be higher than to the NH2 terminus. The WT1/COOH-terminal protein contains four zinc finger domains with homology to other self-proteins. By implication, these homologies may be related to the increased immunological tolerance. Results in patients with CML were similar with antibodies reactive to WT1/full-length protein detectable in serum of 15 of 81 patients (19%). Antibodies reactive with WT1/NH2-terminal protein were present in the serum of all 15, whereas antibodies reactive with WT1/COOH-terminal protein were present in only 3. By contrast to results in leukemia patients, antibodies reactive with WT1/full-length protein were detected in only 2 of 96 normal individuals. The greater incidence of antibody in leukemia patients provides strong evidence that immunization to the WT1 protein occurred as a result of patients bearing malignancy that expresses WT1. These data provide further stimulus to test therapeutic vaccines directed against WT1 with increased expectation that the vaccines will be able to elicit and/or boost an immune response to WT1.
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PMID:WT1-specific serum antibodies in patients with leukemia. 1130 Apr 70

Wild-type Wilms' tumor gene WT1 is expressed at high levels not only in most of acute myelocytic, acute lymphocytic, and chronic myelocytic leukemia, but also in various types of solid tumors including lung cancer. We tested the ability of the gene product (WT1) to serve as a target antigen for tumor specific immunotherapy both in human in vitro system and mouse in vivo system. In the latter, we can evaluate the efficacy and the side effects of WT1 vaccination in vivo. In the human in vitro system, two WT1 peptides that contain HLA-A2.1 binding anchor motifs were determined to bind to HLA-A2.1 molecules. Peripheral blood mononuclear cells (PBMC) from an HLA-A2.1-psitive donor were repeatedly stimulated in vitro with TAP-deficient T2 cells pulsed with each of these two peptides, and CD8-positive cytotoxic T lymphocytes (CTLs) that specifically lyse WT1-expressing, HLA-A2.1-positive tumor cells were induced. Other groups also have succeeded in generating CTLs which specifically lyse WT1-expressing leukemia cells, and which do not inhibit colony-formation of normal hematopoietic cells that express WT1 at physiological levels. In the mouse in vivo system, immunization of C57BL/6 mice with one WT1 peptide with relatively high binding affinity for H-2D(b) molecules, which contain H-2D(b) binding anchor motifs, induced CTLs, which specifically lysed WT1-expressing tumor cells in an H-2D(b)-restricted manner. Furthermore, mice immunized with the WT1 peptide (peptide vaccination) or WT1 cDNA (DNA vaccination) rejected challenges by WT1-expressing tumor cells and survived with no signs of auto-aggression to WT1-expressing normal organs by the induced CTLs. The WT1 protein has been identified as a novel tumor antigen and recent investigations provide a rationale for developing WT1-based adoptive T cell therapy and vaccination against various kinds of malignant neoplasms.
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PMID:WT1 as a novel target antigen for cancer immunotherapy. 1218 20

Among clinicians, initial awareness of the Wilms' tumor gene was limited mostly to pediatric oncologists. Almost a decade ago, overexpression of Wilms' tumor 1 (WT1) was observed in adult acute leukemia. Subsequent studies indicated that WT1 overexpression occurs in most cases of acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS). Limited tissue expression of WT1 in adults suggests that WT1 can be a target for leukemia/MDS therapy. WT1 expression in stem/progenitor cells remains unsettled. However, lack of progenitor cell suppression by WT1 antisense or WT1-specific cytotoxic T cells provide some assurance that WT1 expression in progenitor cells is minimal or absent. Immunotherapy-based WT1 approaches are furthest along in preclinical development. WT1-specific cytotoxic lymphocytes can be generated from normals and leukemic patients. In mice, WT1 vaccines elicit specific immune responses without evidence of tissue damage. In this paper, we review studies validating the immunogenicity of WT1 and propose that leukemia and MDS may be a good clinical model to test the efficacy of a WT1 vaccine.
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PMID:WT1 in acute leukemia, chronic myelogenous leukemia and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies. 1283 18

After allogeneic stem cell transplantation (SCT), we evaluated the use of the Wilms' tumor gene (WT1) as a minimal residual disease (MRD) marker in 32 patients (28 chronic myeloid leukemia, three acute lymphoblastic leukemia and one acute myeloid leukemia). All patients expressed BCR-ABL and the kinetics of WT1 were compared with those of BCR-ABL using real-time quantitative PCR. WT1 expression was seen in the peripheral blood (PB) of healthy controls with a median expression level of 7 x 10(-5) (WT1/ABL ratio). The corresponding values for BCR-ABL-negative and BCR-ABL-positive patient samples were 1 x 10(-4) and 1.6 x 10(-4), respectively. Kinetic studies in individual patients showed that WT1 and BCR-ABL levels usually did not copy each other. In four out of six patients who relapsed, an increase in WT1 from the background level (10(-4)) was observed only at the time of or after relapse, and in two patients increasing WT1 levels were observed before the relapse. In addition, the WT1 values found at the time of relapse were only two logs higher than the background level, indicating a sensitivity of 10(-2). In conclusion, there is a constitutive low expression of WT1 in normal hematopoietic cells. The sensitivity and ability of WT1 to predict a relapse were poor in this study.
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PMID:Poor correlation of kinetics between BCR-ABL and WT1 transcript levels after allogeneic stem cell transplantation. 1525 61


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