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Isoform- and mutation- specific roles of Wilms Tumor 1 in acute myeloid leukemia maintenance

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153865 | GEO | 2021/07/30

REPOSITORIES: GEO

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

2021-07-30 | GSE153864 | GEO

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

2021-07-30 | GSE153861 | GEO

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

2021-07-30 | GSE153860 | GEO

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

2021-07-30 | GSE153863 | GEO

Isoform- and mutation- specific roles of Wilms Tumor 1 in acute myeloid leukemia maintenance

Project description:Isoform- and mutation- specific roles of Wilms Tumor 1 in acute myeloid leukemia maintenance

| PRJNA644368 | ENA

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

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

| PRJNA644364 | ENA

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

Project description:Isoform- and mutation- specific roles of Wilms Tumor 1 in acute myeloid leukemia maintenance (ATAC-Seq)

| PRJNA644365 | ENA

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

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

| PRJNA644371 | ENA

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

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

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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.

2024-07-31 | GSE239734 | GEO

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