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WT1; Wilms tumor 1 (11p13)

Gene Summary

Gene:WT1; Wilms tumor 1
Aliases: GUD, AWT1, WAGR, WT33, NPHS4, WIT-2, EWS-WT1
Location:11p13
Summary:This gene encodes a transcription factor that contains four zinc-finger motifs at the C-terminus and a proline/glutamine-rich DNA-binding domain at the N-terminus. It has an essential role in the normal development of the urogenital system, and it is mutated in a small subset of patients with Wilm's tumors. This gene exhibits complex tissue-specific and polymorphic imprinting pattern, with biallelic, and monoallelic expression from the maternal and paternal alleles in different tissues. Multiple transcript variants have been described. In several variants, there is evidence for the use of a non-AUG (CUG) translation initiation site upstream of and in-frame with the first AUG. Authors of PMID:7926762 also provide evidence that WT1 mRNA undergoes RNA editing in human and rat, and that this process is tissue-restricted and developmentally regulated. [provided by RefSeq, Oct 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:Wilms tumor protein
HPRD
Source:NCBI
Updated:14 March, 2014

Gene
Ontology:

What does this gene/protein do?
WT1 is implicated in:
- adrenal cortex formation
- adrenal gland development
- branching involved in ureteric bud morphogenesis
- C2H2 zinc finger domain binding
- camera-type eye development
- cardiac muscle cell fate commitment
- cellular response to cAMP
- cellular response to gonadotropin stimulus
- cytoplasm
- diaphragm development
- double-stranded DNA binding
- epithelial cell differentiation
- germ cell development
- glomerular basement membrane development
- glomerular visceral epithelial cell differentiation
- glomerulus development
- gonad development
- heart development
- induction of apoptosis
- kidney development
- male genitalia development
- male gonad development
- mesenchymal to epithelial transition
- mesonephros development
- metanephric epithelium development
- metanephric mesenchyme development
- metanephric S-shaped body morphogenesis
- metanephros development
- negative regulation of apoptotic process
- negative regulation of cell growth
- negative regulation of cell proliferation
- negative regulation of female gonad development
- negative regulation of metanephric glomerular mesangial cell proliferation
- negative regulation of transcription from RNA polymerase II promoter
- negative regulation of transcription, DNA-dependent
- negative regulation of translation
- nuclear speck
- nucleic acid binding
- nucleolus
- nucleoplasm
- nucleus
- positive regulation of heart growth
- positive regulation of male gonad development
- positive regulation of metanephric ureteric bud development
- positive regulation of transcription from RNA polymerase II promoter
- positive regulation of transcription, DNA-dependent
- posterior mesonephric tubule development
- protein binding
- regulation of organ formation
- regulation of transcription from RNA polymerase II promoter
- regulation of transcription, DNA-dependent
- RNA binding
- RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription
- RNA splicing
- sequence-specific DNA binding
- sequence-specific DNA binding transcription factor activity
- sex determination
- thorax and anterior abdomen determination
- tissue development
- transcription regulatory region DNA binding
- ureteric bud development
- vasculogenesis
- visceral serous pericardium development
- zinc ion binding
Data from Gene Ontology via CGAP

Pathways:

What pathways are this gene/protein implicaed in?
- Chaperones modulate interferon Signaling Pathway BIOCARTA
- Overview of telomerase protein component gene hTert Transcriptional Regulation BIOCARTA
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

The Wilms' tumour suppressor gene (WT1) gene was first cloned in 1989. The protein it produces is thought to have an important role in normal kidney and gonad development. Mutations in this gene are found in children with familial (inherited) Wilms' tumour and in children with WAGR genitourinary malformations. However, only about 10% of sporadic (non-familial) Wilms' tumours contain a WT1 mutation.

WT1 is overexpressed in a wide range of hematological and solid malignancies, including acute leukaemias where WT1 expression has prosgnostic significance.

Therapeutic use: WT1 is proving to be a promising tumor antigen for the development of a new class of universal cancer vaccines. There are a number of cancer vaccine trials using WT1-targeted immunotherapy in a range of cancers.


Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 March 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 March, 2014 using data from PubMed, MeSH and CancerIndex

Notable

WT1 and Wilms Tumour

Related Publications (492)

WT1 and Acute Myeloid Leukaemia
WT1 is aberrantly over-expressed in AML.
Related Publications (170)

WT1 use in Cancer Immunotherapy Therapy
In a National Cancer Institute prioritization project, WT1 was ranked first in a list of 75 cancer antigens (Cheever et al, 2009) promoting clinical trials of WT1-targeted therapies. There are a number of cancer vaccine trials using WT1-targeted immunotherapy in a range of cancers.Several features of WT1 make it a promising target for immunotherapy (Van Driessche et al, 2012). It is highly expressed in several types of hematological malignancies and solid tumors. Studies using WT1 antisense oligonucleotides have indicated growth inhibition in leukemic and solid tumour cells using treatment with WT1 antisense oligonucleotides. Moreover, WT1 has been shown to have a negative influence on differentiation, but promotes proliferation of progenitor cells. The WT1 protein exhibits high T-cell antigenicity, and loss of WT1 expression can lead to cessation of proliferation or death of cancer cells.
Related Publications (100)

WT1 expression in Childhood Leukemia

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WT1 expression in Myelodysplastic Syndromes

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WT1 expression in Mesothelioma Prognostic

Related Publications (62)

WT1 and Residual Disease

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WT1 expression in Ovarian Cancer

Related Publications (30)

WT1 expression in Non-Small Cell Lung Cancer Prognostic Epigenetics
A number of studies have shown that WT1 expression is relevant in NSCLC. For exampple Nikolaidis et al (2012) identified hypermethylation at p16, TERT, WT1, and RASSF1 as having diagnostic significance in a case-control study of NSCLC. Hayashi et al. (2012) found that low WT1 expression predicted poor prognosis in patients with NSCLC.
Related Publications (21)

WT1 Polymorphism rs16754 in AML
Ho wr al (2014) reported a relationship between prognosis in childhood AML, WT1 expression and WT1 SNP rs16754. In SNP- patients, high WT1 expression predicted decreased survival in univariate, but not multivariate, analysis, due to a preponderance of high-risk cyto/molecular abnormalities in the highest expression group.
Related Publications (14) dbSNP entry

t(11;22)(p13;q12): EWSR1-WT1 in Desmoplastic Small Round Cell Tumour
DSRCT is a rare and an aggressive malignancy characterised by a translocation of the EWSR1 and WT1 genes, resulting in a EWSR1-WT1 fusion protein.
Related Publications (6)

Related Links

Latest Publications: WT1 (cancer-related)

Eneman B, Mekahli D, Audrezet MP, et al.
An unusual presentation of Denys-Drash syndrome due to bigenic disease.
Pediatrics. 2014; 133(1):e252-6 [PubMed] Related Publications
We report a case of Denys-Drash syndrome (DDS) in a 3-month-old girl presenting with bilateral renal cortical cysts mimicking polycystic kidney disease. Genetic analysis revealed a de novo heterozygous missense mutation c.1186G>A (p.Asp396Asn) in the WT1 gene, confirming the diagnosis of DDS. Because multiple renal cysts have never been reported in DDS, we explored several genes responsible for these renal manifestations, such as HNF-1β, PAX2, PKD1, and PKD2. Remarkably, we identified a heterozygous missense variant c.12439A>G (p.Lys4147Glu) in the PKD1 gene. The same variant was found in the patient's mother, who had no renal cysts, and in the grandfather, who had several renal cysts. Mutation prediction programs classified the c.12439A>G variant as being "likely pathogenic." We hypothesize that the severe cystic phenotype in the index patient could be due to the WT1 mutation, enhancing pathogenicity of the "hypomorph" PKD1 allele. A possible role for Wilms tumor suppressor 1 (WT1) in renal cyst development should be considered. From a conceptual point of view, this case shows that an unusual presentation of a known genetic syndrome might point to bigenic inheritance, with unexpected interference of mutated genes causing an uncommon clinical phenotype.


Coosemans A, Vanderstraeten A, Tuyaerts S, et al.
Wilms' Tumor Gene 1 (WT1)--loaded dendritic cell immunotherapy in patients with uterine tumors: a phase I/II clinical trial.
Anticancer Res. 2013; 33(12):5495-500 [PubMed] Related Publications
AIM: Treatment options are limited in uterine cancer, leading to a poor prognosis. Overexpression of Wilms' tumor gene 1 (WT1), the highest ranked tumor antigen, is attractive for immunotherapy.
PATIENTS AND METHODS: Six pre-treated patients with uterine cancer received four weekly vaccines of autologous dendritic cells (DCs) electroporated with WT1 mRNA. Safety, feasibility and immunogenicity were assessed. In cases of response, patients received monthly booster vaccines.
RESULTS: The technique was feasible. One patient had a local allergic reaction. Three out of four Human Leucocyte Antigen-A2 (HLA-A2)-positive patients showed an oncological response; an enrichment of WT1-specific T-cells was observed in two of them. Two HLA-A2-negative patients did not show an oncological or an immunological response.
CONCLUSION: A first series of six patients with uterine cancer treated with WT1 mRNA-electroporated DCs is presented herein. Oncological and immunological responses were observed and are supportive for further research.


Luna I, Such E, Cervera J, et al.
WT1 isoform expression pattern in acute myeloid leukemia.
Leuk Res. 2013; 37(12):1744-9 [PubMed] Related Publications
WT1 plays a dual role in leukemia development, probably due to an imbalance in the expression of the 4 main WT1 isoforms. We quantify their expression and evaluate them in a series of AML patients. Our data showed a predominant expression of isoform D in AML, although in a lower quantity than in normal CD34+ cells. We found a positive correlation between the total WT1 expression and A, B and C isoforms. The overexpression of WT1 in AML might be due to a relative increase in A, B and C isoforms, together with a relative decrease in isoform D expression.

Related: Acute Myeloid Leukemia (AML)


You Y, Li X, Zheng J, et al.
Transcript level of nucleostemin in newly diagnosed acute myeloid leukemia patients.
Leuk Res. 2013; 37(12):1636-41 [PubMed] Related Publications
To clarify the role of nucleostemin (NS) in AML, its transcription levels in bone marrow (BM) samples obtained from 128 newly diagnosed AML patients were analyzed. We determined that the highest NS transcription level was in M1 patients, while the lowest NS transcription level was in M3 patients. NS mRNA expression is positively correlated with blast percentages (%) and CD34, CD117 and CD123 antigen expression in BM samples but is unrelated to the transcription level of WT1. A significant difference in NS expression between poor-risk and better-risk and between poor-risk and intermediate-risk AML patients was found. Our initial data indicated that NS can be used for tracking minimal residual disease (MRD) and is a helpful guide for treatment.

Related: Acute Myeloid Leukemia (AML) Childhood Acute Myeloid Leukaemia AML - Molecular Biology


Coosemans A, Vanderstraeten A, Tuyaerts S, et al.
Immunological response after WT1 mRNA-loaded dendritic cell immunotherapy in ovarian carcinoma and carcinosarcoma.
Anticancer Res. 2013; 33(9):3855-9 [PubMed] Related Publications
BACKGROUND: Dendritic cell (DC)-based immunotherapy is an emerging new treatment option in ovarian cancer, an important cause of cancer-related mortality.
PATIENTS AND METHODS: One patient with ovarian carcinosarcoma (OCS) and one with serous ovarian cancer (SOC) received four weekly vaccinations of autologous DCs electroporated with mRNA coding for the Wilms' tumor gene 1 (WT1). Safety, feasibility and immunogenicity were assessed.
RESULTS: Vaccination was feasible without toxicity. In an ex vivo antigen re-stimulation assay of peripheral blood mononuclear cells, both patients showed increasing cluster of differentiation 137 (CD137+) antigen-specific T-cells and interleukin 10 (IL-10) production post-vaccination. Moreover, interleukin-2 (IL-2) production increased (OCS) as well as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) (SOC). Disease in patients progressed after four vaccines and patients continued with conventional therapies. After cessation of immunotherapy, they had an extended survival of 19 (OCS) and 12 (SOC) months.
CONCLUSION: To our knowledge, we report for the first time the feasibility and T-cell immunogenicity of WT1 mRNA-loaded DC immunotherapy in ovarian cancer.

Related: Cytokines Ovarian Cancer


Rinaldi A, Mensah AA, Kwee I, et al.
Promoter methylation patterns in Richter syndrome affect stem-cell maintenance and cell cycle regulation and differ from de novo diffuse large B-cell lymphoma.
Br J Haematol. 2013; 163(2):194-204 [PubMed] Related Publications
In a fraction of patients, chronic lymphocytic leukaemia (CLL) can transform to Richter syndrome (RS), usually a diffuse large B-cell lymphoma (DLBCL). We studied genome-wide promoter DNA methylation in RS and clonally related CLL-phases of transformed patients, alongside de novo DLBCL (of non-germinal centre B type), untransformed-CLL and normal B-cells. The greatest differences in global DNA methylation levels were observed between RS and DLBCL, indicating that these two diseases, although histologically similar, are epigenetically distinct. RS was more highly methylated for genes involved in cell cycle regulation. When RS was compared to the preceding CLL-phase and with untransformed-CLL, RS presented a higher degree of methylation for genes possessing the H3K27me3 mark and PRC2 targets, as well as for gene targets of TP53 and RB1. Comparison of the methylation levels of individual genes revealed that OSM, a stem cell regulatory gene, exhibited significantly higher methylation levels in RS compared to CLL-phases. Its transcriptional repression by DNA methylation was confirmed by 5-aza-2'deoxycytidine treatment of DLBCL cells, determining an increased OSM expression. Our results showed that methylation patterns in RS are largely different from de novo DLBCL. Stem cell-related genes and cell cycle regulation genes are targets of DNA methylation in RS.

Related: Azacitidine Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology


Ho PA, Alonzo TA, Gerbing RB, et al.
The prognostic effect of high diagnostic WT1 gene expression in pediatric AML depends on WT1 SNP rs16754 status: report from the Children's Oncology Group.
Pediatr Blood Cancer. 2014; 61(1):81-8 [PubMed] Related Publications
BACKGROUND: WT1 is aberrantly over-expressed in most cases of AML. We recently demonstrated that WT1 SNP rs16754 correlates with favorable outcome and high diagnostic WT1 expression in childhood AML. We examined the clinical correlates of diagnostic WT1 expression within a contemporary COG trial and determined whether its prognostic impact differs between SNP+ and SNP- patients.
PROCEDURE: WT1 mRNA expression was measured via qRT-PCR in diagnostic specimens obtained from 225 patients enrolled on COG-AAML03P1. Direct sequencing of WT1 exon 7 was performed to determine SNP rs16754 genotype. WT1 expression was correlated with disease characteristics, SNP status, and outcome.
RESULTS: Patients were categorized into four groups (quartiles: Q1 through Q4) based on diagnostic WT1 expression for analysis. FLT3/ITD (P = 0.017) and WT1 mutations (P < 0.001) both occurred more frequently in patients with the highest WT1 expression. SNP rs16754 frequency did not vary significantly among the quartiles. When all patients were considered, survival outcomes were similar between quartiles. However, when only SNP- patients (n = 150) were analyzed, those with highest WT1 expression (Q4) had the poorest OS (51% vs. 72% for Q1-Q3, P = 0.006) and EFS (35% vs. 54% for Q1-Q3, P = 0.031). Among SNP+ patients (n = 75), survival did not vary significantly between WT1 expression quartiles.
CONCLUSION: Although WT1 expression was not prognostic when all patients were considered together, stratifying patients by SNP rs16754 genotype revealed significant differences in outcome. In SNP- patients, high WT1 expression predicted decreased survival in univariate, but not multivariate, analysis, due to a preponderance of high-risk cyto/molecular abnormalities in the highest expression quartile.

Related: Acute Myeloid Leukemia (AML) Childhood Acute Myeloid Leukaemia AML - Molecular Biology Gemtuzumab (Mylotarg)


Wu C, Zhu W, Qian J, et al.
WT1 promotes invasion of NSCLC via suppression of CDH1.
J Thorac Oncol. 2013; 8(9):1163-9 [PubMed] Related Publications
INTRODUCTION: The Wilms' tumor gene (WT1) has been identified as an oncogene in many malignant diseases, and aberrant WT1 expression has been linked to development, progression, and prognosis of non-small-cell lung cancer (NSCLC). We sought to investigate the underlying mechanism of WT1 and metastasis in NSCLC.
METHODS: Real-time polymerase chain reaction was applied to detect WT1 and CDH1 mRNA in 159 NSCLC samples and corresponding adjacent tissues. Stable clones with overexpression and knockdown of WT1 were generated with plasmid and shRNA via lentivirus technology in H1568 and H1650 NSCLC cell lines. Wound-healing assay, transwell assays, and polymerase chain reaction array were carried out for invasion evaluation. Dual luciferase reporter assay was performed to validate the effect of WT1 on CDH1.
RESULTS: The level of the WT1 mRNA was negatively correlated with that of E-cadherin (CDH1) and associated with pathological stage, metastasis, and survival rate of 159 NSCLC patients. A series of genes were regulated by WT1, and WT1 could suppress CDH1 transcription via direct binding to its promoter and may enhance the invasive ability of H1568 and H1650 NSCLC cell lines.
CONCLUSIONS: WT1 expression was correlated with clinical stage, metastasis, and survival rate in 159 NSCLC patients. Via direct binding to the promoter, WT1 could suppress CDH1 and promote NSCLC invasion.

Related: Apoptosis Non-Small Cell Lung Cancer Lung Cancer


Anelli L, Zagaria A, Coccaro N, et al.
A novel t(4;16)(q25;q23.1) associated with EGF and ELOVL6 deregulation in acute myeloid leukemia.
Gene. 2013; 529(1):144-7 [PubMed] Related Publications
About 50% of acute myeloid leukemia (AML) patients show the occurrence of non-random chromosome rearrangements. Most of the recurrent karyotypic rearrangements in AML have been defined as distinct disease entities in the 2008 World Health Organization (WHO) classification. In this paper we report an AML case showing a novel t(4;16)(q25;q23.1) rearrangement causing the activation of epidermal growth factor (EGF) and elongation of long-chain fatty acids family member 6 (ELOVL6) genes, rather than the generation of a novel fusion gene.

Related: Chromosome 16 Chromosome 4 FISH Acute Myeloid Leukemia (AML)


Hou HA, Lin CC, Chou WC, et al.
Integration of cytogenetic and molecular alterations in risk stratification of 318 patients with de novo non-M3 acute myeloid leukemia.
Leukemia. 2014; 28(1):50-8 [PubMed] Related Publications
Conventionally, acute myeloid leukemia (AML) patients are categorized into good-, intermediate- and poor-risk groups according to cytogenetic changes. However, patients with intermediate-risk cytogenetics represent a largely heterogeneous population regarding treatment response and clinical outcome. In this study, we integrated cytogenetics and molecular mutations in the analysis of 318 patients with de novo non-M3 AML who received standard chemotherapy. According to the mutation status of eight genes, including NPM1, CEBPA, IDH2, RUNX1, WT1, ASXL1, DNMT3A and FLT3, that had prognostic significance, 229 patients with intermediate-risk cytogenetics could be refinedly stratified into three groups with distinct prognosis (P<0.001); patients with good-risk genotypes had a favorable outcome (overall survival, OS, not reached) similar to those with good-risk cytogenetics, whereas those with poor-risk genotypes had an unfavorable prognosis (OS, 10 months) similar to those with poor-risk cytogenetics (OS, 13.5 months), and the remaining patients with other genotypes had an intermediate outcome (OS, 25 months). Integration of cytogenetic and molecular profiling could thus reduce the number of intermediate-risk AML patients from around three-fourth to one-fourth. In conclusion, integration of cytogenetic and molecular changes improves the prognostic stratification of AML patients, especially those with intermediate-risk cytogenetics, and may lead to better decision on therapeutic strategy.

Related: Acute Myeloid Leukemia (AML)


Subbiah V, Brown RE, Jiang Y, et al.
Morphoproteomic profiling of the mammalian target of rapamycin (mTOR) signaling pathway in desmoplastic small round cell tumor (EWS/WT1), Ewing's sarcoma (EWS/FLI1) and Wilms' tumor(WT1).
PLoS One. 2013; 8(7):e68985 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma in adolescents and young adults. The hallmark of this disease is a EWS-WT1 translocation resulting from apposition of the Ewing's sarcoma (EWS) gene with the Wilms' tumor (WT1) gene. We performed morphoproteomic profiling of DSRCT (EWS-WT1), Ewing's sarcoma (EWS-FLI1) and Wilms' tumor (WT1) to better understand the signaling pathways for selecting future targeted therapies.
METHODOLOGY: This pilot study assessed patients with DSRCT, Wilms' tumor and Ewing's sarcoma. Morphoproteomics and immunohistochemical probes were applied to detect: p-mTOR (Ser2448); p-Akt (Ser473); p-ERK1/2 (Thr202/Tyr204); p-STAT3 (Tyr 705); and cell cycle-related analytes along with their negative controls.
PRINCIPAL FINDINGS: In DSRCT the PI3K/Akt/mTOR pathway is constitutively activated by p-Akt (Ser 473) expression in the nuclear compartment of the tumor cells and p-mTOR phosphorylated on Ser 2448, suggesting mTORC2 (rictor+mTOR) as the dominant form. Ewing's sarcoma had upregulated p-Akt and p-mTOR, predominantly mTORC2. In Wilm's tumor, the mTOR pathway is also activated with most tumor cells moderately expressing p-mTOR (Ser 2448) in plasmalemmal and cytoplasmic compartments. This coincides with the constitutive activation of one of the downstream effectors of the mTORC1 signaling pathway, namely p-p70S6K (Thr 389). There was constitutive activation of the Ras/Raf/ERK pathway p-ERK 1/2 (Thr202/Tyr204) expression in the Wilms tumor and metastatic Ewing's sarcoma, but not in the DSRCT.
CONCLUSION: MORPHOPROTEOMIC TUMOR ANALYSES REVEALED CONSTITUTIVE ACTIVATION OF THE MTOR PATHWAY AS EVIDENCED BY: (a) expression of phosphorylated (p)-mTOR, p-p70S6K; (b) mTORC 2 in EWS and DSRCT; (c) ERK signaling was seen in the advanced setting indicating these as resistance pathways to IGF1R related therapies. This is the first morphoproteomic study of such pathways in these rare malignancies and may have potential therapeutic implications. Further study using morphoproteomic assessments of these tumors are warranted.

Related: Desmoplastic Small Round Cell Tumor FLI1 gene Ewing's Sarcoma Signal Transduction Wilms' Tumour Wilms Tumour


Méndez-Catalá CF, Gretton S, Vostrov A, et al.
A novel mechanism for CTCF in the epigenetic regulation of Bax in breast cancer cells.
Neoplasia. 2013; 15(8):898-912 [PubMed] Free Access to Full Article Related Publications
We previously reported the association of elevated levels of the multifunctional transcription factor, CCCTC binding factor (CTCF), in breast cancer cells with the specific anti-apoptotic function of CTCF. To understand the molecular mechanisms of this phenomenon, we investigated regulation of the human Bax gene by CTCF in breast and non-breast cells. Two CTCF binding sites (CTSs) within the Bax promoter were identified. In all cells, breast and non-breast, active histone modifications were present at these CTSs, DNA harboring this region was unmethylated, and levels of Bax mRNA and protein were similar. Nevertheless, up-regulation of Bax mRNA and protein and apoptotic cell death were observed only in breast cancer cells depleted of CTCF. We proposed that increased CTCF binding to the Bax promoter in breast cancer cells, by comparison with non-breast cells, may be mechanistically linked to the specific apoptotic phenotype in CTCF-depleted breast cancer cells. In this study, we show that CTCF binding was enriched at the Bax CTSs in breast cancer cells and tumors; in contrast, binding of other transcription factors (SP1, WT1, EGR1, and c-Myc) was generally increased in non-breast cells and normal breast tissues. Our findings suggest a novel mechanism for CTCF in the epigenetic regulation of Bax in breast cancer cells, whereby elevated levels of CTCF support preferential binding of CTCF to the Bax CTSs. In this context, CTCF functions as a transcriptional repressor counteracting influences of positive regulatory factors; depletion of breast cancer cells from CTCF therefore results in the activation of Bax and apoptosis.

Related: Apoptosis Breast Cancer


Yamauchi T, Negoro E, Lee S, et al.
Detectable Wilms' tumor-1 transcription at treatment completion is associated with poor prognosis of acute myeloid leukemia: a single institution's experience.
Anticancer Res. 2013; 33(8):3335-40 [PubMed] Related Publications
BACKGROUND/AIM: The present retrospective study was conducted to measure Wilms' tumor-1 (WT1) mRNA levels in the peripheral blood of patients with acute myeloid leukemia (AML) in order to examine any association with the clinical outcomes.
PATIENTS AND METHODS: A total of 58 AML patients were evaluated retrospectively in our institution. WT1 transcripts were determined by real-time reverse transcriptase-polymerase chain reaction in peripheral blood samples.
RESULTS: WT1 levels at diagnosis did not vary according to response of induction treatments, and the levels were comparable between the patients with durable remission and the patients with relapse of disease. WT1 levels at the completion of the treatment were higher in the group with relapse of disease than in the group with sustained remission. Detectable WT1 transcripts after the completion of chemotherapy courses were associated with poor prognoses.
CONCLUSION: WT1 mRNA levels at treatment completion may predict for prognosis of AML.

Related: Acute Myeloid Leukemia (AML)


Marani C, Clavio M, Grasso R, et al.
Integrating post induction WT1 quantification and flow-cytometry results improves minimal residual disease stratification in acute myeloid leukemia.
Leuk Res. 2013; 37(12):1606-11 [PubMed] Related Publications
Fifty uniformly treated adult AML patients were analyzed with respect to pre-treatment and post-induction risk factors. Forty-two patients achieving complete hematological remission were assessed for minimal residual disease (MRD) by WT1 gene expression; 34 by flow-cytometry (flow-MRD). Patients who were flow-MRD negative had a better 3-year disease-free (DFS; 79.5% vs. 27.3%; p=.032) compared with patients who were still positive after induction. Interestingly, DFS of flow-MRD positive patients was not related to the amount of flow-detected clone population (≥ or <1%, p=.41) but to WT1 reduction (ΔWT1, 3-year DFS; 46.2% vs. 0% if ΔWT1 was ≥ or < of 1.5 log, p=.001). In AML, combining MRD results provided by WT1 quantification and flow-cytometry improves the reliability of MRD-based prognostic stratification. Similar analyses by further larger studies should be advocated.

Related: Acute Myeloid Leukemia (AML)


Jacobs DI, Mao Y, Fu A, et al.
Dysregulated methylation at imprinted genes in prostate tumor tissue detected by methylation microarray.
BMC Urol. 2013; 13(1):37 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Imprinting is an important epigenetic regulator of gene expression that is often disrupted in cancer. While loss of imprinting (LOI) has been reported for two genes in prostate cancer (IGF2 and TFPI2), disease-related changes in methylation across all imprinted gene regions has not been investigated.
METHODS: Using an Illumina Infinium Methylation Assay, we analyzed methylation of 396 CpG sites in the promoter regions of 56 genes in a pooled sample of 12 pairs of prostate tumor and adjacent normal tissue. Selected LOI identified from the array was validated using the Sequenom EpiTYPER assay for individual samples and further confirmed by expression data from publicly available datasets.
RESULTS: Methylation significantly increased in 52 sites and significantly decreased in 17 sites across 28 unique genes (P < 0.05), and the strongest evidence for loss of imprinting was demonstrated in tumor suppressor genes DLK1, PLAGL1, SLC22A18, TP73, and WT1. Differential expression of these five genes in prostate tumor versus normal tissue using array data from a publicly available database were consistent with the observed LOI patterns, and WT1 hypermethylation was confirmed using quantitative DNA methylation analysis.
CONCLUSIONS: Together, these findings suggest a more widespread dysregulation of genetic imprinting in prostate cancer than previously reported and warrant further investigation.

Related: Prostate Cancer


Miller CL, Anderson DR, Kundu RK, et al.
Disease-related growth factor and embryonic signaling pathways modulate an enhancer of TCF21 expression at the 6q23.2 coronary heart disease locus.
PLoS Genet. 2013; 9(7):e1003652 [PubMed] Free Access to Full Article Related Publications
Coronary heart disease (CHD) is the leading cause of mortality in both developed and developing countries worldwide. Genome-wide association studies (GWAS) have now identified 46 independent susceptibility loci for CHD, however, the biological and disease-relevant mechanisms for these associations remain elusive. The large-scale meta-analysis of GWAS recently identified in Caucasians a CHD-associated locus at chromosome 6q23.2, a region containing the transcription factor TCF21 gene. TCF21 (Capsulin/Pod1/Epicardin) is a member of the basic-helix-loop-helix (bHLH) transcription factor family, and regulates cell fate decisions and differentiation in the developing coronary vasculature. Herein, we characterize a cis-regulatory mechanism by which the lead polymorphism rs12190287 disrupts an atypical activator protein 1 (AP-1) element, as demonstrated by allele-specific transcriptional regulation, transcription factor binding, and chromatin organization, leading to altered TCF21 expression. Further, this element is shown to mediate signaling through platelet-derived growth factor receptor beta (PDGFR-β) and Wilms tumor 1 (WT1) pathways. A second disease allele identified in East Asians also appears to disrupt an AP-1-like element. Thus, both disease-related growth factor and embryonic signaling pathways may regulate CHD risk through two independent alleles at TCF21.

Related: Signal Transduction Wilms' Tumour Wilms Tumour


Vidovic K, Ullmark T, Rosberg B, et al.
Leukemia associated mutant Wilms' tumor gene 1 protein promotes expansion of human hematopoietic progenitor cells.
Leuk Res. 2013; 37(10):1341-9 [PubMed] Related Publications
The transcription factor Wilms' tumor gene 1 (WT1) is highly expressed in the majority of leukemias, suggesting a role in leukemogenesis. Acquired WT1 mutations are reported as an independent predictor of poor clinical outcome, and mutations resulting in deletion of the entire DNA-binding zinc-finger domain (WT1delZ), is the most common type. The aim of this study was to study cellular effects of WT1(delZ) that may contribute to an oncogenic phenotype. We found that expression of WT1(delZ) supported proliferation of human hematopoietic CD34(+) progenitor cells. Moreover, WT1(delZ) transduced cells expressed erythroid markers, including raised levels of STAT5, independently of addition of erythropoietin. At the global gene expression level, WT1(delZ) caused upregulation of genes related to cell division and genes associated with erythroid maturation, in the absence of added erythropoietin. Our results indicate that WT1(delZ) promotes cell proliferation and expansion of progenitor cells, consistent with a possible role in leukemogenesis.

Related: Leukemia


Tsotakos NE, Sagnou M, Kotsopoulou ES, et al.
Glucose-induced gradual phenotypic modulation of cultured human glomerular epithelial cells may be independent of Wilms' tumor 1 (WT1).
BMC Cell Biol. 2013; 14:28 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Renal podocytes form the main filtration barrier possessing a unique phenotype maintained by proteins including podocalyxin and nephrin, the expression of which is suppressed in pathological conditions. We used an in vitro model of human glomerular epithelial cells (HGEC) to investigate the role of high glucose in dysregulating the podocytic epithelial phenotype and determined the time needed for this change to occur.
RESULTS: In our in vitro podocyte system changes indicating podocyte dedifferentiation in the prolonged presence of high glucose included loss of podocalyxin, nephrin and CD10/CALLA concomitant with upregulation of mesenchymal vimentin. Our study demonstrates for the first time that podocyte-specific markers undergo changes of expression at different time intervals, since glucose-mediated podocalyxin downregulation is a progressive process that precedes downregulation of nephrin expression. Finally we demonstrate that high glucose permanently impaired WT1 binding to the podocalyxin gene promoter region but did not affect WT1 binding on the nephrin gene promoter region.
CONCLUSION: The presence of high glucose induced a phenotypic conversion of podocytes resembling partial dedifferentiation. Our study demonstrates that dysregulation of the normal podocytic phenotype is an event differentially affecting the expression of function-specific podocytic markers, exhibiting downregulation of the epithelial marker CD10/CALLA and PC first, followed by stably downregulated nephrin. Furthermore, it is herein suggested that WT1 may not be directly involved with upregulation of previously reduced PC and nephrin expression.

Related: Kidney Cancer Wilms' Tumour Wilms Tumour


Metzeler KH, Maharry K, Kohlschmidt J, et al.
A stem cell-like gene expression signature associates with inferior outcomes and a distinct microRNA expression profile in adults with primary cytogenetically normal acute myeloid leukemia.
Leukemia. 2013; 27(10):2023-31 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
Acute myeloid leukemia (AML) is hypothesized to be sustained by self-renewing leukemia stem cells (LSCs). Recently, gene expression signatures (GES) from functionally defined AML LSC populations were reported, and expression of a 'core enriched' (CE) GES, representing 44 genes activated in LCSs, conferred shorter survival in cytogenetically normal (CN) AML. The prognostic impact of the CE GES in the context of other molecular markers, including gene mutations and microRNA (miR) expression alterations, is unknown and its clinical utility is unclear. We studied associations of the CE GES with known molecular prognosticators, miR expression profiles, and outcomes in 364 well-characterized CN-AML patients. A high CE score (CE(high)) associated with FLT3-internal tandem duplication, WT1 and RUNX1 mutations, wild-type CEBPA and TET2, and high ERG, BAALC and miR-155 expression. CE(high) patients had a lower complete remission (CR) rate (P=0.003) and shorter disease-free (DFS, P<0.001) and overall survival (OS, P<0.001) than CE(low) patients. These associations persisted in multivariable analyses adjusting for other prognosticators (CR, P=0.02; DFS, P<0.001; and OS, P<0.001). CE(high) status was accompanied by a characteristic miR expression signature. Fifteen miRs were upregulated in both younger and older CE(high) patients, including miRs relevant for stem cell function. Our results support the clinical relevance of LSCs and improve risk stratification in AML.

Related: Acute Myeloid Leukemia (AML)


Krönke J, Bullinger L, Teleanu V, et al.
Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia.
Blood. 2013; 122(1):100-8 [PubMed] Related Publications
Mutations in the nucleophosmin 1 (NPM1) gene are considered a founder event in the pathogenesis of acute myeloid leukemia (AML). To address the role of clonal evolution in relapsed NPM1-mutated (NPM1mut) AML, we applied high-resolution, genome-wide, single-nucleotide polymorphism array profiling to detect copy number alterations (CNAs) and uniparental disomies (UPDs) and performed comprehensive gene mutation screening in 53 paired bone marrow/peripheral blood samples obtained at diagnosis and relapse. At diagnosis, 15 aberrations (CNAs, n = 10; UPDs, n = 5) were identified in 13 patients (25%), whereas at relapse, 56 genomic alterations (CNAs, n = 46; UPDs, n = 10) were detected in 29 patients (55%) indicating an increase in genomic complexity. Recurrent aberrations acquired at relapse included deletions affecting tumor suppressor genes (ETV6 [n = 3], TP53 [n = 2], NF1 [n = 2], WT1 [n = 3], FHIT [n = 2]) and homozygous FLT3 mutations acquired via UPD13q (n = 7). DNMT3A mutations (DNMT3Amut) showed the highest stability (97%). Persistence of DNMT3Amut in 5 patients who lost NPM1mut at relapse suggests that DNMT3Amut may precede NPM1mut in AML pathogenesis. Of note, all relapse samples shared at least 1 genetic aberration with the matched primary AML sample, implying common ancestral clones. In conclusion, our study reveals novel insights into clonal evolution in NPM1mut AML.

Related: Chromosome 13 Chromosome 9 Acute Myeloid Leukemia (AML)


Takeuchi T, Ohishi Y, Imamura H, et al.
Ovarian transitional cell carcinoma represents a poorly differentiated form of high-grade serous or endometrioid adenocarcinoma.
Am J Surg Pathol. 2013; 37(7):1091-9 [PubMed] Related Publications
Ovarian transitional cell tumors include Brenner tumors (BTs) and transitional cell carcinoma (TCC; non-BTs) according to the most recent World Health Organization classification. However, it remains a matter of debate whether TCC represents a distinct entity or a morphologic variant of high-grade serous adenocarcinoma (HG-SC). The purpose of this study was to resolve the above question by clarifying the morphologic, immunohistochemical, and molecular features of TCC. We reviewed 488 cases of epithelial ovarian carcinomas and reclassified them on the basis of the most recent World Health Organization classification with the modifications proposed by Köbel and colleagues, and 35 cases of TCC were identified; 25 and 6 TCCs were admixed with HG-SC and endometrioid adenocarcinoma (EC), respectively, and the remaining 4 cases were pure TCC. TCC components were not observed in any clear cell carcinomas or mucinous adenocarcinomas. Only 2 cases of malignant BT were identified. In addition to TCCs, malignant BTs, and related adenocarcinomas, benign and borderline BTs were included in the following immunohistochemical and molecular analyses. Immunohistochemically, pure TCCs, TCCs admixed with HG-SC, and pure HG-SCs were characterized by frequent aberrant p53 expression (diffuse or null pattern) and WT1+/ER+/PR+/IMP2+ immunophenotype, whereas BTs, including benign, borderline, and malignant BTs, were characterized by lack of aberrant p53 expression and WT1-/ER-/PR-/IMP2- immunophenotype. In contrast to the BTs, pure ECs and TCCs admixed with EC showed an ER+/PR+ immunophenotype. Nearly all the tumors with a TP53 gene mutation by molecular analysis showed aberrant p53 staining patterns. In conclusion, TCC is not a distinct entity but a poorly differentiated form of serous or EC, as (1) most TCCs coexist with HG-SC (mostly) or EC (occasionally), and (2) the immunophenotype and molecular features are similar to those of HG-SC or EC but different from those of BTs.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Ovarian Cancer TP53


Zhao XS, Yan CH, Liu DH, et al.
Combined use of WT1 and flow cytometry monitoring can promote sensitivity of predicting relapse after allogeneic HSCT without affecting specificity.
Ann Hematol. 2013; 92(8):1111-9 [PubMed] Related Publications
Either WT1 or leukemia-associated aberrant immune phenotypes (LAIPs) was one of the minimal residual disease (MRD) parameters used to predict leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We first evaluated the clinical value of various positive MRD standards for accurately indicating relapse based on WT1 and FCM data in adult patients with acute leukemia (AL). In total, 824 AL patients treated with allo-HSCT were enrolled in this study. We compared the sensitivity and specificity of diverse, multiple-criteria MRD prognostic standards based on WT1 and FCM assays. Higher sensitivity was achieved without a loss of specificity when MRDco+, which was defined as two consecutive WT10.6+ or FCM+ or both WT10.6+ and FCM+ in the same sample within a year posttransplantation, was used as the positive MRD standard. Similar results were observed, even in 484 patients who had both abnormal WT1 and LAIPs values before transplant. A multivariate analysis showed that MRDco+ was an independent risk factor for leukemia relapse after transplant in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The combined use of FCM and WT1 monitoring could distinguish between patients with low and high risks of relapse. Various positive MRD standards were useful for guiding intervention.

Related: Leukemia


Yoon JH, Kim HJ, Shin SH, et al.
BAALC and WT1 expressions from diagnosis to hematopoietic stem cell transplantation: consecutive monitoring in adult patients with core-binding-factor-positive AML.
Eur J Haematol. 2013; 91(2):112-21 [PubMed] Related Publications
No consecutive analysis of BAALC and WT1 expressions associated with core-binding factor AML (CBF-AML) from diagnosis to hematopoietic stem cell transplantation (HSCT) has yet been reported. We investigated BAALC and WT1 expressions using a method of real-time quantitative polymerase chain reaction (RQ-PCR) at diagnosis, after induction chemotherapy, at pre-HSCT, and at post-HSCT period in 45 consecutive patients [t(8,21) (n = 28), inv(16) (n = 17)], who received HSCT as a post-remission treatment. BAALC and WT1 RQ-PCR decrement ratio (DR) was also calculated at post-induction chemotherapy, at pre-HSCT, and at post-HSCT compared with the diagnostic level. Higher BAALC expression at diagnosis showed significantly inferior OS (P = 0.031), EFS (P = 0.011), and higher CIR (P = 0.002) rates. At post-HSCT, both higher BAALC and WT1 expressions showed significantly inferior OS (P = 0.005, 0.016), EFS (P = 0.002, 0.006), and higher CIR (P = 0.001, 0.003) rates. A subgroup of t(8;21) showing higher BAALC and WT1 expressions at post-HSCT were also associated with inferior OS (P = 0.018, 0.015) and higher CIR rates (P = 0.019, 0.011). While BAALC DR showed no significant results on outcomes, WT1 DR more than 2-log at post-HSCT showed significantly lower CIR rate (P = 0.028). This study showed that higher post-HSCT BAALC and WT1 expressions in patients with CBF-AML may be good markers of minimal residual disease for the prediction of survival and relapse after HSCT.

Related: Acute Myeloid Leukemia (AML)


Buglyó G, Méhes G, Vargha G, et al.
WT1 microdeletion and slowly progressing focal glomerulosclerosis in a patient with male pseudohermaphroditism, childhood leukemia, Wilms tumor and cerebellar angioblastoma.
Clin Nephrol. 2013; 79(5):414-8 [PubMed] Related Publications
The Wilms tumor 1 (WT1) gene is currently in focus by pediatric nephrologists as its mutations are associated with nephrotic syndrome, especially as part of complex clinical entities like Denys-Drash or Frasier syndrome. Renal failure may also develop in young WAGR patients, whose condition is attributed to a deletion at chromosomal region 11p13. However, only limited data exist on WT1 microdeletions. A 30-year-old male patient, with a history of genital malformations, a Wilms tumor manifested during the treatment of acute lymphoid leukemia (ALL) at the age of 4, and a cerebellar angioblastoma, was referred with proteinuria and a reduced glomerular filtration rate (GFR). Kidney biopsy revealed FSGS. Although all WT1 exons were amplified with polymerase chain reaction (PCR) and sequenced, none of them showed a mutation. However, an formalin-fixed, paraffin- embedded (FFPE) tissue sample of the patient's childhood Wilms tumor showed WT1- positivity restricted to the renal tumor cells, so the WT1 gene was investigated further. Using quantitative reverse transcription PCR (qRT-PCR), the gene was found to be present in only one copy in the patient's genomic DNA sample, while both copies were detected in both parents. In the patient's sister, the proximal region of WT1 was shown to have an extra copy. Evidence suggests that a heterozygous microdeletion of the gene WT1 is responsible for the patient's disease. It seems reasonable to assume a possible abnormality affecting meiotic crossing over at the WT1 locus in one of the parents.

Related: Kidney Cancer Acute Lymphocytic Leukemia (ALL) Wilms' Tumour Wilms Tumour


Wang X, Dai H, Wang Q, et al.
EZH2 mutations are related to low blast percentage in bone marrow and -7/del(7q) in de novo acute myeloid leukemia.
PLoS One. 2013; 8(4):e61341 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
The purpose of the present work was to determine the incidence and clinical implications of somatic EZH2 mutations in 714 patients with de novo acute myelogenous leukemia by sequencing the entire coding region. EZH2 mutations were identified in 13/714 (1.8%) of AML patients were found to be more common in males (P = 0.033). The presence of EZH2 mutations was significantly associated with lower blast percentage (21-30%) in bone marrow (P<0.0001) and -7/del(7q) (P = 0.025). There were no differences in the incidence of mutation in 13 genes, ASXL1, CBL, c-KIT, DNMT3A, FLT3, IDH1, IDH2, MLL, NPM1, NRAS, RUNX1, TET2, and WT1, between patients with and without EZH2 mutations. No difference in complete remission, event-free survival, or overall survival was observed between patients with and without EZH2 mutation (P>0.05). Overall, these results showed EZH2 mutation in de novo acute myeloid leukemia as a recurrent genetic abnormality to be associated with lower blast percentage in BM and -7/del(7q).

Related: Chromosome 7 Acute Myeloid Leukemia (AML) Childhood Acute Myeloid Leukaemia AML - Molecular Biology


Nomdedéu JF, Hoyos M, Carricondo M, et al.
Bone marrow WT1 levels at diagnosis, post-induction and post-intensification in adult de novo AML.
Leukemia. 2013; 27(11):2157-64 [PubMed] Related Publications
We retrospectively assessed whether normalized bone marrow WT1 levels could be used for risk stratification in a consecutive series of 584 acute myeloid leukemia (AML) patients. A cutoff value of 5065 copies at diagnosis identified two prognostic groups (overall survival (OS): 44 ± 3 vs 36 ± 3%, P=0.023; leukemia-free survival (LFS): 47 ± 3 vs 36 ± 4%, P=0.038; and cumulative incidence of relapse (CIR): 37 ± 3 vs 47 ± 4%, P=:0.043). Three groups were identified on the basis of WT1 levels post-induction: Group 0 (WT1 between 0 and 17.5 copies, 134 patients, OS: 59 ± 4%, LFS:59 ± 4% and CIR: 26 ± 4%); Group 1 (WT1 between 17.6 and 170.5 copies, 160 patients, OS: 48 ± 5%, LFS:41 ± 4% and CIR: 45 ± 4%); and Group 2 (WT1 >170.5 copies, 71 patients, OS: 23 ± 6%, LFS: 19 ± 7% and CIR: 68 ± 8%) (P<0.001). Post-intensification samples distinguished three groups: patients with WT1 >100 copies (47 patients, 16%); an intermediate group of patients with WT1 between 10 and 100 copies (148 patients, 52%); and a third group with WT1 <10 copies (92 patients, 32%). Outcomes differed significantly in terms of OS (30 ± 7%, 59 ± 4%, 72 ± 5%), LFS (24 ± 7%, 46 ± 4%, 65 ± 5%) and relapse probability (CIR 72 ± 7%, 45 ± 4%, 25 ± 5%), all P<0.001. WT1 levels in bone marrow assayed using the standardized ELN method provide relevant prognostic information in de novo AML.

Related: Acute Myeloid Leukemia (AML)


Yoon JH, Kim HJ, Shin SH, et al.
Serial measurement of WT1 expression and decrement ratio until hematopoietic cell transplantation as a marker of residual disease in patients with cytogenetically normal acute myelogenous leukemia.
Biol Blood Marrow Transplant. 2013; 19(6):958-66 [PubMed] Related Publications
Using real-time quantitative PCR, we monitored Wilms tumor gene 1 (WT1) expression from diagnosis to hematopoietic stem cell transplantation (HSCT) in adult patients with cytogenetically normal acute myelogenous leukemia (CN-AML) and FLT3-ITD and NPM1 mutations. The values at diagnosis were evaluated in 104 patients. Data collected after induction chemotherapy were available for all patients, but only 68 patients were treated with HSCT. Significant WT1 expression cut-offs were determined by receiver operation characteristic curve analysis, and rates of overall survival (OS) and disease-free survival (DFS) were estimated. WT1 decrement ratios (DR) at postinduction chemotherapy and at pre- and post-HSCT compared with the diagnostic level were calculated. Higher WT1 expression at diagnosis, postinduction chemotherapy, and pre-HSCT showed inferior OS (P = .015, <.001, and .002) and DFS (P = .006, <.001, and .003). The cut-offs were determined at the median for diagnostic WT1 expression and at the 25% level from the top for other time points excluding post-HSCT. The WT1 DR ≥ 1-log after induction chemotherapy showed superior OS and DFS (P = .009 and .002) and WT1 DR ≥ 1-log preceding HSCT also showed superior OS and DFS (P = .009 and .003). Results of WT1 DR were consistently applicable in each subgroup with higher (≥ 1.0) and lower (<1.0) WT1 expression at diagnosis and also in NPM1-wild-type/FLT3-ITD-negative CN-AML. The WT1 DR therefore predicted survival outcomes after HSCT more accurately than did the diagnostic WT1 expression. WT1 expression may serve as a reliable marker for residual disease and WT1 DR as a prognostic indicator, particularly in NPM1-wild-type/FLT3-ITD-negative CN-AML. These measures may be applied throughout the course of treatment and even after HSCT.

Related: Acute Myeloid Leukemia (AML)


Weber G, Gerdemann U, Caruana I, et al.
Generation of multi-leukemia antigen-specific T cells to enhance the graft-versus-leukemia effect after allogeneic stem cell transplant.
Leukemia. 2013; 27(7):1538-47 [PubMed] Article available free on PMC after 01/07/2014 Related Publications
Adoptive immunotherapy with ex vivo expanded T cells is a promising approach to prevent or treat leukemia. Myeloid leukemias express tumor-associated antigens (TAA) that induce antigen-specific cytotoxic T lymphocyte (CTL) responses in healthy individuals. We explored the feasibility of generating TAA-specific CTLs from stem cell donors of patients with myeloid leukemia to enhance the graft-versus-leukemia effect after stem cell transplantation. CTL lines were manufactured from peripheral blood of 10 healthy donors by stimulation with 15mer peptide libraries of five TAA (proteinase 3 (Pr3), preferentially expressed antigen in melanoma, Wilms tumor gene 1 (WT1), human neutrophil elastase (NE) and melanoma-associated antigen A3) known to be expressed in myeloid leukemias. All CTL lines responded to the mix of five TAA and were multi-specific as assessed by interferon-γ enzyme-linked immunospot. Although donors showed individual patterns of antigen recognition, all responded comparably to the TAAmix. Immunogenic peptides of WT1, Pr3 or NE could be identified by epitope mapping in all donor CTL lines. In vitro experiments showed recognition of partially human leukocyte antigen (HLA)-matched myeloid leukemia blasts. These findings support the development of a single clinical grade multi-tumor antigen-specific T-cell product from the stem cell source, capable of broad reactivity against myeloid malignancies for use in donor-recipient pairs without limitation to a certain HLA-type.


Grossmann V, Haferlach C, Nadarajah N, et al.
CEBPA double-mutated acute myeloid leukaemia harbours concomitant molecular mutations in 76·8% of cases with TET2 and GATA2 alterations impacting prognosis.
Br J Haematol. 2013; 161(5):649-58 [PubMed] Related Publications
Acute myeloid leukaemia (AML) with CEBPA mutations is listed as a provisional entity in the current World Health Organization classification. A difference in clinical outcome between single- (sm) and double-mutated (dm) cases has been reported, whereupon CEBPAdm cases were shown to be associated with better overall survival (OS). The occurrence and prognostic impact of concomitant molecular mutations in addition to CEBPAdm has not been assessed until now with exception of GATA2 mutations. Here, we investigated a cohort of 95 AML CEBPAdm cases for concomitant mutations. TET2 was found to be most frequently mutated (34·0%) gene, followed by GATA2 (21·0%), WT1 (13·7%), DNMT3A (9·6%), ASXL1 (9·5%), NRAS (8·4%), KRAS (3·2%), IDH1/2 (6·3%), FLT3-internal tandem duplication (6·3%), FLT3-tyrosine kinase domain (2·1%), NPM1 (2·1%), and RUNX1 (1/94). Patients harbouring additional mutations in the TET2 gene showed significantly worse OS than TET2 wild-type cases (P = 0·035), whereas GATA2-mutated patients showed improved OS (P = 0·032). Serial analyses were performed for 39 CEBPAdm cases with concomitant mutations. Here, we observed that CEBPA mutations present the primary pathogenetic event in the majority of cases (76·9%). Further, a distinct gene expression profile (GEP) was confirmed for CEBPAdm versus CEBPAsm or CEBPA wild-type cases while no significant changes in GEP were observed related to additional mutations within the CEBPAdm AML.

Related: Acute Myeloid Leukemia (AML) TET2 gene


Lin Y, Fujiki F, Katsuhara A, et al.
HLA-DPB1*05: 01-restricted WT1332-specific TCR-transduced CD4+ T lymphocytes display a helper activity for WT1-specific CTL induction and a cytotoxicity against leukemia cells.
J Immunother. 2013; 36(3):159-70 [PubMed] Related Publications
Wilms tumor gene 1 (WT1) is overexpressed in various malignant neoplasms, and has been demonstrated as an attractive target for cancer immunotherapy. We previously reported the identification of a WT1 protein-derived, 16-mer helper peptide WT1332 that could elicit Th1-type CD4+ T-cell response and bind to multiple HLA class II molecules. In this study, we examined the feasibility of adoptive therapy using CD4+ T cells that were transduced an HLA-DPB1*05:01-restricted, WT1332-specific T-cell receptor (TCR). HLA-DPB1*05:01-restricted, WT1332-specific TCR-transduced CD4+ T cells were successfully generated using lentiviral vector and exhibited strong proliferative response and Th1-type cytokine production in response to WT1332 peptide, WT1 protein, or WT1-expressing tumor cell lysate. Furthermore, the WT1332-specific TCR-transduced CD4+ T cells lysed HLA-DPB1*05:01-positive, WT1-expressing human leukemia cells through granzyme B/perforin pathway. Furthermore, stimulation of peripheral blood mononuclear cells with both HLA-A*24:02-restricted cytotoxic T lymphocytes-epitope peptide (modified 9-mer WT1235 peptide, WT1235m) and WT1332 helper peptide in the presence of WT1332-specific TCR-transduced CD4+ T cells strikingly enhanced the induction of WT1235m-specific cytotoxic T lymphocytes. Thus, these results demonstrated the feasibility of immunotherapy based on adoptive transfer of WT1332-specific TCR-transduced CD4+ T cells for the treatment of leukemia.

Related: Leukemia


Further References

Van Driessche A, Berneman ZN, Van Tendeloo VF
Active specific immunotherapy targeting the Wilms' tumor protein 1 (WT1) for patients with hematological malignancies and solid tumors: lessons from early clinical trials.
Oncologist. 2012; 17(2):250-9 [PubMed] Free Access to Full Article Related Publications
There is a growing body of evidence that Wilms' tumor protein 1 (WT1) is a promising tumor antigen for the development of a novel class of universal cancer vaccines. Recently, in a National Cancer Institute prioritization project, WT1 was ranked first in a list of 75 cancer antigens. In this light, we exhaustively reviewed all published cancer vaccine trials reporting on WT1-targeted active specific immunotherapy in patients with hematological malignancies and solid tumors. In all clinical trials, vaccine-induced immunological responses could be detected. Importantly, objective clinical responses (including stable disease) were observed in 46% and 64% of evaluable vaccinated patients with solid tumors and hematological malignancies, respectively. Immunogenicity of WT1-based cancer vaccines was demonstrated by the detection of a specific immunological response in 35% and 68% of evaluable patients with solid tumors and hematological malignancies, respectively. In order to become part of the armamentarium of the modern oncologist, it will be important to design WT1-based immunotherapies applicable to a large patient population, to standardize vaccination protocols enabling systematic review, and to further optimize the immunostimulatory capacity of the vaccine components. Moreover, improved immunomonitoring tools that reveal clinically relevant T-cell responses will further shape the ideal WT1 immunotherapy strategy. In conclusion, the clinical results obtained so far in WT1-targeted cancer vaccine trials reveal an untapped potential for inducing cancer immunity with minimal side effects and hold promise for a new adjuvant treatment against residual disease and against cancer relapse.

Related: Haematological Malignancies & Realted Disorders Cancer Prevention and Risk Reduction


Cheever MA, Allison JP, Ferris AS, et al.
The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research.
Clin Cancer Res. 2009; 15(17):5323-37 [PubMed] Related Publications
The purpose of the National Cancer Institute pilot project to prioritize cancer antigens was to develop a well-vetted, priority-ranked list of cancer vaccine target antigens based on predefined and preweighted objective criteria. An additional aim was for the National Cancer Institute to test a new approach for prioritizing translational research opportunities based on an analytic hierarchy process for dealing with complex decisions. Antigen prioritization involved developing a list of "ideal" cancer antigen criteria/characteristics, assigning relative weights to those criteria using pairwise comparisons, selecting 75 representative antigens for comparison and ranking, assembling information on the predefined criteria for the selected antigens, and ranking the antigens based on the predefined, preweighted criteria. Using the pairwise approach, the result of criteria weighting, in descending order, was as follows: (a) therapeutic function, (b) immunogenicity, (c) role of the antigen in oncogenicity, (d) specificity, (e) expression level and percent of antigen-positive cells, (f) stem cell expression, (g) number of patients with antigen-positive cancers, (h) number of antigenic epitopes, and (i) cellular location of antigen expression. None of the 75 antigens had all of the characteristics of the ideal cancer antigen. However, 46 were immunogenic in clinical trials and 20 of them had suggestive clinical efficacy in the "therapeutic function" category. These findings reflect the current status of the cancer vaccine field, highlight the possibility that additional organized efforts and funding would accelerate the development of therapeutically effective cancer vaccines, and accentuate the need for prioritization.

Related: Cancer Prevention and Risk Reduction USA


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