Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the first clones of the Wilms tumor 1 (WT1) gene, WT33, was isolated from a B cell leukemia cell line in 1990. Now, 12 years on, WT1 has emerged as a potentially important target for antileukemic therapies. Our understanding of the role that WT1 plays during normal hematopoiesis is still limited, and there is a large amount of conflicting data concerning the precise manner in which WT1 gene expression contributes to leukemogenesis. However, interest in this field has intensified in the past 5 years. This review surveys the progress made in this area.
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PMID:A review of the Wilms' tumor 1 gene (WT1) and its role in hematopoiesis and leukemia. 1220 48

Tumor antigen-specific CD4+ and CD8+ T lymphocytes, especially interferon-gamma (IFN-gamma)-producing type-1 helper T (Th1) and type-1 cytotoxic T (Tc1) cells, play a crucial role in tumor eradication. Adoptive transfer using tumor-specific Th1 and Tc1 cells is a promising therapeutic strategy for tumor immunotherapy. However, its clinical application has been hampered because of difficulties in generating tumor-specific Th1 cells from patients with tumors. To overcome this problem, we have developed an efficient method to prepare tumor-specific Th1 and Tc1 cells. T-cell receptor (TCR) alpha and beta genes obtained from an HLA-A24-restricted, Wilms tumor 1 (WT1) peptide-specific Tc clone were lentivirally transduced to polyclonally activated Th1 and Tc1 cells. As expected, TCR gene-modified Tc1 cells showed cytotoxicity and IFN-gamma production in response to peptide-loaded lymphoblastoid cell lines, WT1 gene-transduced cells, and freshly isolated leukemia cells expressing both WT1 and HLA-A24. Surprisingly, we further demonstrated that Th1 cells transduced with HLA-class I-restricted TCR genes also showed both cytotoxicity and cytokine production in an HLA-A24-restricted manner. In contrast to gene-modified Tc1 cells, Th1 cells produced high amounts of interleukin-2 (IL-2) in addition to IFN-gamma, which is beneficial for induction of antitumor cellular immunity. Thus, TCR gene-modified HLA-class I-restricted Th1 and Tc1 cells are a powerful strategy for the application to adoptive immunotherapy of human cancer.
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PMID:Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes. 1579 Jul 89

The tumor suppressor gene wt1 (Wilms tumor 1) encodes a zinc finger transcription factor reported to be expressed in many tumors, including mesotheliomas, carcinomas, and acute leukemias. However, WT1 expression in non-Hodgkin lymphomas (NHLs) has not been studied. The authors assessed for WT1 expression in six lymphoma/leukemia cell lines using Western blot methods after subcellular fractionation. We also assessed for WT1 expression in 167 NHLs using immunohistochemical methods. The B-cell NHLs analyzed were 18 diffuse large B-cell lymphomas, 13 marginal zone B-cell lymphomas, 9 small lymphocytic lymphomas, (DLBCLs), 8 follicular lymphomas, 6 mantle cell lymphomas, 5 Burkitt lymphomas, 3 lymphoplasmacytic lymphomas, and 2 B-cell lymphoblastic lymphomas. The T-cell NHLs analyzed were 43 anaplastic large cell lymphomas (ALCLs), 26 peripheral T-cell lymphomas unspecified, 13 angioimmunoblastic T-cell lymphomas, 6 cutaneous ALCLs, 6 cases of mycosis fungoides, 5 extranodal NK/T-cell lymphomas of nasal type, and 4 T-cell lymphoblastic lymphomas. WT1 levels were higher in cytoplasmic extracts than in nuclear extracts of the Karpas 299 and SU-DHL-1 lymphoma cell lines but were higher in nuclear extracts than in the cytoplasmic extracts of the Jurkat, HH, U-937, and K562 leukemia cell lines. In NHLs, WT1 was positive in 4 of 5 (80%) Burkitt lymphomas, 9 of 12 (75%) ALK-positive ALCLs, 3 of 6 (50%) lymphoblastic lymphomas (2 of 4 T-cell, 1 of 2 B-cell), 14 of 31 (45%) ALK-negative ALCLs, 6 of 18 (33%) DLBCLs, and 1 of 6 (17%) cutaneous ALCLs. WT1 was negative in all other NHLs tested. WT1 immunoreactivity was primarily cytoplasmic in all positive NHLs except T-cell lymphoblastic lymphoma. In conclusion, WT1 protein is frequently detected in the cytoplasm of a subset of high-grade NHLs.
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PMID:Differential expression of WT1 gene product in non-Hodgkin lymphomas. 1589 24

The inhibitory roles of nitric oxide (NO) in T cell proliferation have been observed and studied extensively over the last two decades. Despite efforts, the fundamental pathway by which NO exerts its inhibitory actions remains to be elucidated although recent evidence suggests that the transcription factor Wilms tumor 1 (WT1) may be important. WT1 has been linked to numerous developmental pathways in particular nephrogenesis. Due to its roles in development and cell proliferation, polymorphisms within the WT1 gene can result in malignancies such as leukemia and Wilms tumor. WT1 functions as a transcriptional regulator and its activity is controlled through phosphorylation by protein kinase A (PKA). PKA-dependent WT1 phosphorylation results in translocation of WT1 from the nucleus to the cytosol, a process that interferes with WT1 transcriptional activities. In the current study we demonstrate that WT1 is expressed in human lymphocytes. Using the proliferative compound PHA we induced T cell proliferation and growth correlated with an increase in the expression of WT1 measured by RT-PCR, flow cytometry and immunoblot. Co-stimulation with the NO donor SNOG at concentrations of 0, 100, 300 and 600 microM reduced in a concentration dependent way the PHA-induced upregulation of WT1 that correlated with a reduction in T cell proliferation. We conclude that WT1 might be an important component of the NO-dependent regulation of T lymphocyte proliferation and potential function.
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PMID:Human lymphocytes express the transcriptional regulator, Wilms tumor 1: the role of WT1 in mediating nitric oxide-dependent repression of lymphocyte proliferation. 1786 19

In allogeneic hematopoietic stem cell transplantation (AHSCT) graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect are closely but not invariably linked. Thus, harnessing donor lymphocyte mediated GVL immunity and separating it from GVHD is of particular interest. Based on results obtained in murine models we have explored the CD95-mediated activation-induced cell death (AICD) strategy to selectively deplete alloreactivity in human donor T lymphocytes in vitro. Following stimulation of CD3(+) T cells isolated from HLA-A* 0201-positive donors with HLA or minor histocompatibility antigen mismatched hematopoietic or nonhematopoietic cells in the presence of agonistic anti-CD95 antibody, we achieved efficient and selective allodepletion across major and minor histocompatibility mismatched barriers. Residual alloreactivity was in the range of 10% and 25% using hematopoietic cells and primary keratinocytes as alloantigen-presenting cells, respectively. CD8(+) T cells specific for HLA-A * 0201-associated cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Wilms tumor 1 peptide epitopes were retained at significant numbers within the allodepleted donor lymphocyte subsets. Additionally, CD4(+) FoxP3(+) regulatory T cells persisted after the allodepletion procedure. Our results show that AICD induced by an agonistic anti-CD95 antibody might be useful to generate allodepleted donor lymphocyte products with preserved beneficial immune functions for patients undergoing AHSCT.
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PMID:Depletion of alloreactive donor T lymphocytes by CD95-mediated activation-induced cell death retains antileukemic, antiviral, and immunoregulatory T cell immunity. 1815 66

Although oncogenic functions and the clinical significance of Wilms tumor 1 (WT1) have been extensively studied in acute leukemia, the regulatory mechanism of its transcription still remains to be determined. We found a significant correlation among the amounts of WT1, GATA-1 and GATA-2 mRNAs from leukemia and solid tumor cell lines. Overexpression and small interfering RNA (siRNA) transfection experiments of GATA-1 and GATA-2 showed that these GATA transcription factors could induce WT1 expression. Promoter analysis showed that the 5' promoter did not explain the different WT1 mRNA levels between cell lines. The 3' enhancer, especially the distal sites out of six putative GATA binding sites located within the region, but not the intron 3 enhancer, were essential for the WT1 mRNA level. Electrophoretic mobility shift assay (EMSA) showed both GATA-1 and GATA-2 bound to these GATA sites. Besides acute leukemia cell lines, solid tumor cell lines including, TYK-nu-cPr also showed a high level of WT1 mRNA. We showed that GATA-2 expression is a determinant of WT1 mRNA expression in both TYK-nu-cPr cells and HL60 cells without GATA-1 expression. Taken together, these results suggest that GATA-1 and/or GATA-2 binding to a GATA site of the 3' enhancer of WT1 played an important role in WT1 gene expression.
Leukemia 2009 Jul
PMID:GATA-1 and GATA-2 binding to 3' enhancer of WT1 gene is essential for its transcription in acute leukemia and solid tumor cell lines. 1921 33

We previously reported the adverse prognostic impact of Wilms tumor 1 gene (WT1) mutations in younger adult cytogenetically normal acute myeloid leukemia (CN-AML). Here, we investigated 243 older (> or = 60 years) primary CN-AML patients. WT1 mutated (WT1mut) patients (7%) had FLT3-ITD more frequently (P < .001), lower hemoglobin (P = .01), higher white blood cell count (P = .03) and percentage blood blasts (P = .03), and a shorter overall survival (P = .08) than WT1 wild-type (WT1wt) patients. Comparing older and younger WT1mut patients, they had similar pretreatment characteristics and outcome. By contrast, among WT1wt CN-AML, younger patients had a significantly better outcome. A WT1 mutation-associated gene-expression signature, reported here for the first time, included CD96, a leukemia stem cell-specific marker, and genes involved in gene regulation (eg, MLL, PML, and SNRPN) and in proliferative and metabolic processes (eg, INSR, IRS2, and PRKAA1), supporting the role of mutated WT1 in deregulating multiple homeostatic processes. Our results indicate that WT1mut CN-AML represents a distinct entity with poor treatment response across age groups. This study has been registered at www.clinicaltrials.gov as #NCT00900224.
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PMID:Mutations of the Wilms tumor 1 gene (WT1) in older patients with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. 2044 68

The aberrant overexpression of Wilms tumor 1 (WT1) in myeloid leukemia plays an important role in blast cell survival and resistance to chemotherapy. High expression of WT1 is also associated with relapse and shortened disease-free survival in patients. However, the mechanisms by which WT1 expression is regulated in leukemia remain unclear. Here, we report that heat shock protein 90 (Hsp90), which plays a critical role in the folding and maturation of several oncogenic proteins, associates with WT1 protein and stabilizes its expression. Pharmacologic inhibition of Hsp90 resulted in ubiquitination and subsequent proteasome-dependant degradation of WT1. RNAi-mediated silencing of WT1 reduced the survival of leukemia cells and increased the sensitivity of these cells to chemotherapy and Hsp90 inhibition. Furthermore, Hsp90 inhibitors 17-AAG [17-(allylamino)-17-demethoxygeldanamycin] and STA-9090 significantly reduced the growth of myeloid leukemia xenografts in vivo and effectively down-regulated the expression of WT1 and its downstream target proteins, c-Myc and Bcl-2. Collectively, our studies identify WT1 as a novel Hsp90 client and support the crucial role for the WT1-Hsp90 interaction in maintaining leukemia cell survival. These findings have significant implications for developing effective therapies for myeloid leukemias and offer a strategy to inhibit the oncogenic functions of WT1 by clinically available Hsp90 inhibitors.
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PMID:Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias. 2065 Oct 72

The favorable graft-versus-leukemia (GVL) effect that occurs after stem cell transplantation suggests that T cells can eradicate leukemia blasts. T cells specifically recognize peptides and exert an antileukemia effect. Several leukemia-associated antigens (LAAs) have been found to be overexpressed in malignant cells from patients with acute or chronic leukemia leading to the generation of peptide-based leukemia immunotherapy. Peptide vaccination with LAAs, whose expression is low in normal tissue, such as the receptor for hyaluronic acid-mediated motility (RHAMM), Wilms tumor 1 (WT1), proteinase-3 (PR-3) and the breakpoint cluster region-Abelson (bcr-abl) has been reported to induce leukemia-specific T-cell responses in patients with a variety of hematological malignancies. Moreover, the immune responses achieved after vaccination positively correlated with good clinical outcomes, that is complete remission. Large efforts have been made to optimize the dose and format of vaccines, as well as their adjuvants, in small pilot trials. In this article we summarize clinical Phase I and II peptide vaccination trials with RHAMM, WT1, PR-3 and bcr-abl for leukemia patients.
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PMID:Clinical peptide vaccination trials for leukemia patients. 2169

Recently, DNA methyltransferase 3A (DNMT3A) mutations have been identified in acute myeloid leukemia (AML), the highest frequency being found within cytogenetically normal (CN) AML. In this study, diagnostic samples from 123 adults younger than 60 years with primary CN-AML homogeneously treated in the Acute Leukemia French Association-9801 and -9802 trials were screened for mutations in DNMT3A-conserved domains by direct sequencing. Patients were also assessed for the presence of FLT3 (fms-like tyrosine kinase receptor-3), NPM1 (nucleophosmin), CEBPA, WT1 (Wilms tumor 1), IDH1 (isocitrate dehydrogenase 1) and IDH2 mutations. Thirty-eight mutations were detected in 36 patients (29%): 36 nucleotide substitutions, mostly affecting amino-acid residue R882 and two frameshift deletions. DNMT3A mutations were significantly associated with the French-American-British subtypes M4/M5 and the presence of NPM1 mutations. In the whole cohort, DNMT3A mutated patients had a shorter event-free survival (5-year EFS: 13% vs 32%, P = 0.02) and overall survival (5-year OS: 23% vs 45%, P = 0.02) compared with DNMT3A wild-type patients. In multivariate analysis including age, white blood cell count, NPM1/FLT3-internal tandem duplication/CEBPA risk group and DNMT3A mutational status, the presence of a DNMT3A mutation remained an independent adverse prognostic factor for EFS and OS, suggesting that testing for DNMT3A mutations could help further improve risk stratification in CN-AML.
Leukemia 2012 Jun
PMID:Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association. 2228 88


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