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Isoform- and mutation- specific roles of Wilms Tumor 1 in acute myeloid leukemia maintenance (DNAse I hypersensitivity)

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: GSE153863 | 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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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.

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Upregulation of HOXA3 by Isoform-Specific Wilms Tumor 1 Drives Chemotherapy Resistance in Acute Myeloid Leukemia

Project description:Upregulation of the Wilms' Tumor 1 (WT1) gene is common in acute myeloid leukemia (AML) and is associated with poor prognosis, including disease relapse, decreased overall survival (OS), and chemotherapy resistance. WT1 produces 12 primary transcripts through different translation initiation sites and alternative splicing, but the specific transcripts and mechanisms responsible for chemoresistance are unknown. We found that overexpression of short WT1 transcripts lacking exon 5 with and without the KTS motif (sWT1+/- and sWT1-/-) led to reduced cell growth. However, only sWT1+/- resulted in decreased CD71 expression, G1 arrest, and cytarabine resistance. Primary AML patient cells with low CD71 expression exhibit relative resistance to cytarabine, suggesting that CD71 may serve as a potential biomarker for cytarabine therapy. RNAseq differential gene expression analysis identified two transcription factors, HOXA3 and GATA2, that are specifically upregulated in sWT1+/- cells. Overexpression of either HOXA3 or GATA2 reproduced the effects of sWT1+/-, including decreased cell growth, G1 arrest, reduced CD71 expression, and cytarabine resistance. Furthermore, sWT1+/-, HOXA3, and GATA2 regulate cell growth and cytarabine sensitivity in a context-dependent manner, likely dependent on HOXA3 expression. HOXA3 expression is significantly correlated with chemotherapy response, OS, and ELN subtypes in NPM1-negative leukemia specimens. Overexpression of HOXA3 leads to drug resistance against a broad spectrum of chemotherapeutic agents. Our results suggest that WT1 modulates drug sensitivity in an isoform-specific manner by promoting HOXA3 expression. Both HOXA3 mRNA and CD71 cell surface expression could serve as potential biomarkers for predicting responses to cytarabine-based treatment in AML.

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

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

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2017-04-04 | PXD003283 | Pride

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

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