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Isoform- and mutation- specific roles of Wilms Tumor 1 in acute myeloid leukemia maintenance (RNA-Seq)

ABSTRACT: Acute myeloid leukemia (AML) is caused by recurrent mutations in members of the gene regulatory and signalling machinery subverting hematopoietic differentiation. We previously showed that each AML sub-type displays a different gene regulatory network with specific transcription factor families playing distinct roles in maintaining the leukemic phenotype. Here we show that the transcription factor WT1 forms a major node in the gene regulatory networks of multiple AML sub-types. It is frequently mutated and up-regulated in AML and its expression is pedictive for relapse. The WT1 protein exists as different isoforms which we show here to harbor differential chromatin binding and contrasting biological activity, including directing differential splicing. For two main AML subtypes we demonstrate that WT1 responds to oncogenic signaling and is part of a signaling-responsive transcription factor hub that controls AML growth. WT1 therefore plays a central and wide-spread role in AML biology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153864 | GEO | 2021/07/30

REPOSITORIES: GEO

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Isoform- and mutation- specific roles of Wilms Tumor 1 in acute myeloid leukemia maintenance (ChIP-Seq)

Project description:Acute myeloid leukemia (AML) is caused by recurrent mutations in members of the gene regulatory and signalling machinery subverting hematopoietic differentiation. We previously showed that each AML sub-type displays a different gene regulatory network with specific transcription factor families playing distinct roles in maintaining the leukemic phenotype. Here we show that the transcription factor WT1 forms a major node in the gene regulatory networks of multiple AML sub-types. It is frequently mutated and up-regulated in AML and its expression is pedictive for relapse. The WT1 protein exists as different isoforms which we show here to harbor differential chromatin binding and contrasting biological activity, including directing differential splicing. For two main AML subtypes we demonstrate that WT1 responds to oncogenic signaling and is part of a signaling-responsive transcription factor hub that controls AML growth. WT1 therefore plays a central and wide-spread role in AML biology.

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Wilms' tumor 1 WT1(-KTS) isoform time course induction in U2OS cells

2007-06-21 | GSE5117 | GEO

Transcription profiling of human Wilms tumor 1 WT1(-KTS) isoform time series induction in U2OS cells

Project description:The Wilms' tumor suppressor gene (WT1) encodes a zinc finger transcription factor that plays important roles during development of several organs including metanephric kidneys. A number of WT1 target genes have been identified, but the detailed mechanisms by which WT1 orchestrates renal development remain elusive. To identify WT1 target genes relevant to development, genome-wide expression profiling was performed using oligonucleotide microarrays representing 39,000 human transcripts Experiment Overall Design: Sample_source_name: UB27 cells, U2OS cells with Tetracycline-repressible WT1(-KTS) expression Experiment Overall Design: Sample_characteristics: U2OS cell line (osteosarcoma; female), Tetracycline-repressible WT1(-KTS) expression, time-course induction Experiment Overall Design: of WT1(-KTS) expression Experiment Overall Design: Sample_description: WT1(-KTS) expression was induced for 4, 8 or 12 Experiment Overall Design: hrs and the expression profile of each time-points was compared to the Experiment Overall Design: uninduced sample (0 hr).

2008-06-13 | E-GEOD-5117 | biostudies-arrayexpress

Global binding of isoforms of Wilms' Tumor gene 1 and H3K4me3 in K562 cells

Project description:Background: Wilms' tumor gene 1 (WT1) acts as an oncogene in acute myeloid leukemia (AML). A naturally occurring alternative splice event between zinc fingers three and four, removing or retaining three amino acids (KTS), is believed to change the DNA binding affinity of WT1. Altered balance between WT1 -KTS and WT1 +KTS expression associates with poor prognosis in AML. Methods: We characterized the DNA binding patterns of biotin-tagged WT1 -KTS and WT1 +KTS in K562 cells by chromatin immunoprecipitation and deep sequencing (ChIP-seq). Results: We discovered that WT1 -KTS preferentially binds near transcription start sites (TSS) and in enhancers, whereas WT1 +KTS binds within gene bodies. Additionally, we observed a significant overlap between WT1 -KTS and WT1 +KTS target genes, despite the binding sites being distinct. Motif analysis showed enrichment of two TRANSFAC derived motif matrices within peaks for both isoforms, and enrichment of several previously published WT1 motifs which, however, differed between isoforms. Additional analyses showed that WT1 -KTS and WT1 +KTS target genes are transcribed to a higher extent than non-targets, and involved in cell proliferation, cell death, and development. Conclusions: Our results provide the first evidence that WT1 -KTS and WT1 +KTS bind principally different regions of the genome, yet share target genes. Our results indicate isoform-specific regulation of processes related to cell proliferation and differentiation, consistent with the involvement of WT1 in AML.

2016-12-24 | GSE81009 | GEO

Oligonucleotide expression microarray data for analysis of Wilms tumor 1 gene (WT1) mutations in cytogenetically normal acute myeloid leukemia (AML) patient samples

Project description:Oligonucleotide expression microarray data used for expression signature associated with WT1 mutations in cytogenetically normal AML patient samples

2011-06-17 | E-TABM-1020 | biostudies-arrayexpress

Oviductal fluid LC-MS/MS - The Wilms tumor protein Wt1 contributes to female fertility by regulating oviductal proteostasis

Project description:After fertilization the developing mammalian embryo migrates through the oviduct before it implants in the uterus. In order to prevent tubal pregnancy or failed implantation, development and migration of the embryo has to be tightly coordinated1. The precise molecular basis for the regulation of this maternal-embryonic interaction is largely unknown. Here we show that the Wilms tumor suppressor protein Wt1 is a critical regulator of the interaction between the maternal environment and the early embryo. Our results indicate that subfertility in Wt1ko/+ females is a maternal effect caused by the Wt1-dependent de-regulation of Prss29, encoding a serine protease. Notably, blocking Prss29 activity was sufficient to rescue subfertility in Wt1ko/+ female mice indicating Prss29 as a critical factor in female fertility. Furthermore, we have identified a missense mutation in a patient with idiopathic infertility leading to an amino acid exchange within the zinc finger domain of WT1 and resulting in reduced DNA binding. We demonstrate that Wt1 represses expression of Prss29 and that its de-repression and precocious expression in the oviduct interferes with pre-implantation development. Our study reveals a novel role for Wt1 in early mammalian development and identifies proteases as critical mediators of the maternal-embryonic crosstalk. We believe that our data regarding the importance of a proteostatic environment in the oviduct are also relevant for female fertility in humans. We anticipate that our findings will form the basis for the identification of further causes of idiopathic infertility.

2017-04-04 | PXD003283 | Pride

The Wilms' tumour 1 transcription factor regulates epigenetic states via DNA methyltransferase 3A

Project description:The Wilms' tumour 1 transcription factor regulates epigenetic states via DNA methyltransferase 3A. The data consists of two Nimblegen promoter/CpG island microarrays hybridized with MCIP DNA immunoprecipitated from either a HEK293-derived cell line expressing a heterologous WT1 cDNA (W210) or a control cell line containing the expression vector (IP100), both hybridized against input DNA.

2012-11-05 | E-GEOD-39713 | biostudies-arrayexpress

Transcription profiling of human WT1-mutant versus WT1 wild-type Wilms tumors

Project description:Gain-of-function mutations in exon 3 of beta-catenin (CTNNB1) are specific for Wilms' tumors that have lost WT1, but 50% of WT1-mutant cases lack such "hot spot" mutations. To ask whether stabilization of beta-catenin might be essential after WT1 loss, and to identify downstream target genes, we compared expression profiles in WT1-mutant versus WT1 wild-type Wilms' tumors. Supervised and nonsupervised hierarchical clustering of the expression data separated these two classes of Wilms' tumor. The WT1-mutant tumors overexpressed genes encoding myogenic and other transcription factors (MOX2, LBX1, SIM2), signaling molecules (TGFB2, FST, BMP2A), extracellular Wnt inhibitors (WIF1, SFRP4), and known beta-catenin/TCF targets (FST, CSPG2, CMYC). Beta-Catenin/TCF target genes were overexpressed in the WT1-mutant tumors even in the absence of CTNNB1 exon 3 mutations, and complete sequencing revealed gain-of-function mutations elsewhere in the CTNNB1 gene in some of these tumors, increasing the overall mutation frequency to 75%. Lastly, we identified and validated a novel direct beta-catenin target gene, GAD1, among the WT1-mutant signature genes. These data highlight two molecular classes of Wilms' tumor, and indicate strong selection for stabilization of beta-catenin in the WT1-mutant class. Beta-Catenin stabilization can initiate tumorigenesis in other systems, and this mechanism is likely critical in tumor formation after loss of WT1. Experiment Overall Design: Identification of WNT/Beta-Catenin or WT1 target genes. 39 individual samples.

2008-06-14 | E-GEOD-6120 | biostudies-arrayexpress

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