Upregulation of HOXA3 by Isoform-Specific Wilms Tumor 1 Drives Chemotherapy Resistance in Acute Myeloid Leukemia
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ABSTRACT:
PROVIDER: PRJNA1000638 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25469853_1.fastq.gz | Fastqsanger.gz | |||
| SRR25469853_2.fastq.gz | Fastqsanger.gz | |||
| SRR25469854_1.fastq.gz | Fastqsanger.gz | |||
| SRR25469854_2.fastq.gz | Fastqsanger.gz | |||
| SRR25469855_1.fastq.gz | Fastqsanger.gz |
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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
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 Keywords: Wilms' tumor 1 (WT1) gene, -KTS isoform; time course
2007-06-21 | GSE5117 | GEO
Project description:Patients with Wilms tumors are efficiently treated by chemotherapy; however, tumors with mutant WT1 genes show a poor volume response. Here we used an unbiased gene expression profiling approach and identified a novel mechanism of conventional chemotherapy that explains how the cure of these patients is brought about. Transcription profiling of an untreated WT1 mutant Wilms tumor (Wilms10) and a corresponding lung metastasis that was detected after long-term chemotherapy, revealed the induction of a myogenic transcriptional network with concomitant down-regulation of cell cycle genes. Cell culture experiments showed convincingly that the Wilms10 tumor cells from this lung metastasis had lost their growth potential due to an induction of terminal skeletal muscle differentiation by chemotherapy. These results were confirmed using a set of Wilms tumors with mutant WT1 genes that were treated by preoperative chemotherapy. We conclude here that chemotherapy-induced terminal skeletal muscle differentiation of Wilms tumors with concomitant loss of growth potential enables the cure of Wilms tumor patients with WT1 mutations in the clinical setting. We have shown before that cell lines derived from Wilms tumors with WT1 mutations have characteristic features of mesenchymal stem cells and it will be of great interest to evaluate whether other tumor types with stem cell features show a differentiation reponse to chemotherapy.
2018-06-17 | GSE63616 | GEO
Project description:Abstract: Background: MiRNA signatures in human sera have been reported for various tumor diseases. Here we generated miRNA profiles analyzing 1205 mature miRNA transcripts of serum samples of Wilms tumor patients, taken prior and after chemotherapy according to SIOP protocol 2001. Using a feature subset selection filter approach we identified a minimal number of miRNAs with a maximum contribution for the classification between treated and untreated patients and between patients and controls. Results: Analyzing 1205 mature miRNAs, we separated controls and Wilms tumor patients prior chemotherapy with an accuracy of 0.81. We obtained a similar accuracy (0.82) for the separation between controls and sera of Wilms tumor patients after preoperative chemotherapy. We identified 23 miRNAs that were differentially expressed in both comparisons. Subset selection improved the overall classification accuracy between controls and Wilms tumor patients prior and after chemotherapy to 0.94 and 0.91, respectively. Subset selection also allowed separating between Wilms tumor patients prior and after chemotherapy with an accuracy of 0.98. Conclusion: Our analysis identified serum based miRNA signatures that allowed separating between controls, untreated Wilms tumor patients, and Wilms tumor patients after chemotherapy with high accuracy for each of these comparisons.
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Project description:Blood-borne miRNA signatures have recently been reported for various tumor diseases. Here, we compared the miRNA signature in Wilms tumor patients prior to and after preoperative chemotherapy according to the SIOP protocol 2001. We did not find a significant difference between the miRNA signatures of both groups. However, both Wilms tumor patients prior to and after chemotherapy showed a miRNA signature different from that of healthy controls. The signature of Wilms tumor patients prior to chemotherapy showed an accuracy of 97.5% and of patients after chemotherapy an accuracy of 97.0%, each as compared to healthy controls. Our results provide evidence for a blood-borne Wilms tumor miRNA signature largely independent of four weeks preoperative chemotherapy treatment.
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Project description:Blood-borne miRNA signatures have recently been reported for various tumor diseases. Here, we compared the miRNA signature in Wilms tumor patients prior to and after preoperative chemotherapy according to the SIOP protocol 2001. We did not find a significant difference between the miRNA signatures of both groups. However, both Wilms tumor patients prior to and after chemotherapy showed a miRNA signature different from that of healthy controls. The signature of Wilms tumor patients prior to chemotherapy showed an accuracy of 97.5% and of patients after chemotherapy an accuracy of 97.0%, each as compared to healthy controls. Our results provide evidence for a blood-borne Wilms tumor miRNA signature largely independent of four weeks preoperative chemotherapy treatment. This project analyzes peripheral blood profiles of Wilms tumor patients and controls in order to detect specific profiles. n=19 normal controls and n=23 Wilms tumor patients were screened for the complete miRNA repertoire. Please note that each miRNA has been measured in seven replicates and the median of the replica has been computed.
2013-07-22 | E-GEOD-38419 | biostudies-arrayexpress
Project description:The aim of the study was to identify key transcriptional regulators that might be responsible for the increased resistance to chemotherapy of blastemal Wilms tumors.
2020-04-28 | GSE98334 | GEO
Project description:This study shows for the first time that the FOXP3Î3 isoform is preferentially expressed in bladder cancer and induces a more aggressive and luminal isoform is preferentially expressed in bladder cancer and induces a more aggressive and luminal regulation of cancer differentiation and the plasticity amongst cancer subtypes which can be leveraged to optimize therapeutic regimens. These findings also identify a novel molecular marker as a putative companion diagnostic to guide therapy and target to undermine chemotherapy resistance. examination of RNA-Seq in two bladder cancer cell lines
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Project description:Aberrant splicing is a hallmark of many cancers, including Acute Myeloid Leukemia (AML), but its role in post-treatment relapse remains poorly understood. Here, we analyzed the alternative splicing landscape of 19 AML patients during chemotherapy treatment. We found an upregulation of the long isoform of the transcription factor RUNX1 (also known as RUNX1C) in relapsed cohorts, which conferred chemotherapy resistance. Notably, these patients showed elevanted intragenic DNA methylation at the RUNX1 proximal promoter, thereby activating RUNX1C transcript through its alternative distal promoter. Mechanistically the N-terminus region of RUNX1C is required to promote chemoresistance by regulating a distinct RUNX1 transciptional program. Among these target genes, B-cell translocation gene 2 (BTG2) mediates a quiescent-like phenotype by deadenylating ribosomal RNAs to reduce global protein synthesis. Lastly, we harnessed orthogonal RNA-targeting strategies to target RUNX1C isoform, which led to augmented chemotherapy efficacy. Collectively, our finidngs delineate a transcriptional circuity orchestrated by a transcription factor isoform that underpins chemotherapy responsiveness and a potential therapeutic strategy to mitigate disease recurrence.
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