STAT5BN642H is a driver mutation for T-cell neoplasia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA413088 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5189310.fastq.gz | Fastqsanger.gz | |||
| SRR5189311.fastq.gz | Fastqsanger.gz | |||
| SRR5189302.fastq.gz | Fastqsanger.gz | |||
| SRR5189312.fastq.gz | Fastqsanger.gz | |||
| SRR5189303.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:STAT5BN642H is a driver mutation for T-cell neoplasia (RRBS)
| PRJNA413050 | ENA
Project description:The most frequent mutation in STAT5B is the Asp642His (N642H) mutation that was found in >90 leukemic/lymphoma patients. The development of novel treatment against STAT5BN642H has been hindered by the unavailability of a suitable model and the lack of the direct causal effect of STAT5BN642H on T-cell neoplasia development. We herein demonstrate that mice expressing human STAT5BN642H in the hematopoietic compartment rapidly develop leukemia/lymphoma. The disease is fully transplantable and characterized by the expansion of CD8+ T-cells. hSTAT5BN642H displays persistent and enhanced tyrosine phosphorylation upon cytokine stimulation. This leads to drastic changes in the gene expression profile accompanied by specific alterations in DNA methylation patterns that result in the acceleration of cell cycle progression. hSTAT5BN642H transcriptional activities in T-cell can be inhibited by inhibition of upstream kinases or transcriptional coregulaters, including JAKs, HDACs and BET Bromodomain containing protein. In particular, treatment with ruxolitinib, a JAK kinase inhibitor dramatically reduced tyrosine phosphorylation of hSTAT5BN642H resulting in decreased organ infiltration in vivo. We conclude that hSTAT5BN642H is sufficient to cause leukemia in vivo and JAK inhibitors are potential therapy for leukemic patients with the hSTAT5BN642H.
2023-01-14 | GSE104557 | GEO
Project description:The most frequent mutation in STAT5B is the Asp642His (N642H) mutation that was found in >90 leukemic/lymphoma patients. The development of novel treatment against STAT5BN642H has been hindered by the unavailability of a suitable model and the lack of the direct causal effect of STAT5BN642H on T-cell neoplasia development. We herein demonstrate that mice expressing human STAT5BN642H in the hematopoietic compartment rapidly develop leukemia/lymphoma. The disease is fully transplantable and characterized by the expansion of CD8+ T-cells. hSTAT5BN642H displays persistent and enhanced tyrosine phosphorylation upon cytokine stimulation. This leads to drastic changes in the gene expression profile accompanied by specific alterations in DNA methylation patterns that result in the acceleration of cell cycle progression. hSTAT5BN642H transcriptional activities in T-cell can be inhibited by inhibition of upstream kinases or transcriptional coregulaters, including JAKs, HDACs and BET Bromodomain containing protein. In particular, treatment with ruxolitinib, a JAK kinase inhibitor dramatically reduced tyrosine phosphorylation of hSTAT5BN642H resulting in decreased organ infiltration in vivo. We conclude that hSTAT5BN642H is sufficient to cause leukemia in vivo and JAK inhibitors are potential therapy for leukemic patients with the hSTAT5BN642H.
2020-02-24 | GSE93847 | GEO
Project description:STAT5B is often mutated in hematopoietic malignancies. The most frequent STAT5B mutation, Asp642His (N642H), has been found in over 90 leukemia and lymphoma patients. Here, we used the Vav1 promoter to generate transgenic mouse models that expressed either human STAT5B or STAT5BN642H in the hematopoietic compartment. While STAT5B-expressing mice lacked a hematopoietic phenotype, the STAT5BN642H-expressing mice rapidly developed T cell neoplasms. Neoplasia manifested as transplantable CD8+ lymphoma or leukemia, indicating that the STAT5BN642H mutation drives cancer development. Persistent and enhanced levels of STAT5BN642H tyrosine phosphorylation in transformed CD8+ T cells led to profound changes in gene expression that were accompanied by alterations in DNA methylation at potential histone methyltransferase EZH2-binding sites. Aurora kinase genes were enriched in STAT5BN642H-expressing CD8+ T cells, which were exquisitely sensitive to JAK and Aurora kinase inhibitors. Together, our data suggest that JAK and Aurora kinase inhibitors should be further explored as potential therapeutics for lymphoma and leukemia patients with the STAT5BN642H mutation who respond poorly to conventional chemotherapy.
| S-EPMC5749501 | biostudies-literature
Project description:We found a novel MEN1 p. R21Afs mutaion in a multiple endocrine neoplasia type 1 family. To investigate the pathogenic function of p.R21Afs MEN1 mutation, the leukocyte transcriptoma profilings derived from MEN1 patients with heterozygote p.R21Afs MEN1 mutation was compared with the unaffected relatives without p.R21Afs MEN1 mutation.
2023-02-01 | GSE221993 | GEO
Project description:We investigated the cause of gastrointestinal neoplasia in a man who developed adenocarcinoma of the ampulla of Vater at the age of 34, followed almost three decades later by adenomatous polyps and invasive adenocarcinomas of both the colon and stomach. Premature chromatid separation, mosaic variegated aneuploidy (MVA), combined with structural chromosome abnormalities were detected in his cells. We identified a homozygous intronic mutation, c.2386-11A>G in BUB1B which creates a de novo splice site that is favored over the authentic site. This study expands the phenotype of BUB1B mutations and MVA to include common adult-onset cancers and provides evidence for the interdependency of APC and BUBR1 proteins in humans. 2 biological replicates of 7 samples (lymphoblastoid cell line (LCL) of the affected proband, fibroblasts of the affected proband, LCLs from 2 relatives of the proband, LCLs from 2 unaffected controls, fibroblasts from 1 control) were processed at the same time.
2010-06-16 | E-GEOD-22206 | biostudies-arrayexpress
Project description:All cells in an individual are related to one another by a bifurcating lineage tree, in which each node is an ancestral cell that divided into two, each branch connects two nodes, and the root is the zygote. When a somatic mutation occurs in an ancestral cell, all its descendants carry the mutation, which can then serve as a lineage marker for the phylogenetic reconstruction of tumor progression. Using this concept, we investigate cell lineage relationships and genetic heterogeneity of pre-invasive neoplasias compared to invasive carcinomas.We deeply sequenced over a thousand phylogenetically informative somatic variants in 66 morphologically independent samples from six patients that represent a spectrum of normal, early neoplasia, carcinoma in situ, and invasive carcinoma. For each patient, we obtained a highly resolved lineage tree that establishes the phylogenetic relationships among the pre-invasive lesions and with the invasive carcinoma.The trees reveal lineage heterogeneity of pre-invasive lesions, both within the same lesion, and between histologically similar ones. On the basis of the lineage trees, we identified a large number of independent recurrences of PIK3CA H1047 mutations in separate lesions in four of the six patients, often separate from the diagnostic carcinoma.Our analyses demonstrate that multi-sample phylogenetic inference provides insights on the origin of driver mutations, lineage heterogeneity of neoplastic proliferations, and the relationship of genomically aberrant neoplasias with the primary tumors. PIK3CA driver mutations may be comparatively benign inducers of cellular proliferation.
| S-EPMC4410742 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-02-24 | GSE104577 | GEO
Project description:Cervical intraepithelial neoplasia (CIN), also known as cervical dysplasia, is premalignant lesions of the cervical squamous cell carcinoma (CSCC) that shows abnormal growth of squamous cells in the cervix epithelium. Given the evidence suggesting that differences may exist between CIN and CSCC, we hypothesize that progression may be mediated by subpopulation selection or by acquisition of additional alterations, including gene mutations or chromosomal alterations. In this study, we analyzed cervical CIN, microinvasive carcinoma (MIC) and CSCC by whole-exome sequencing and array-comparative genomic hybridization (array-CGH) and found that CIN genomes harbored fewer mutations (especially fewer driver mutations) and copy number alterations (CNAs), suggesting that additional genomic alterations might burst onto the CIN genome at the final stage of CIN progression to CSCC or an early stage of CSCC.
2014-12-31 | GSE60067 | GEO
Project description:We investigated the cause of gastrointestinal neoplasia in a man who developed adenocarcinoma of the ampulla of Vater at the age of 34, followed almost three decades later by adenomatous polyps and invasive adenocarcinomas of both the colon and stomach. Premature chromatid separation, mosaic variegated aneuploidy (MVA), combined with structural chromosome abnormalities were detected in his cells. We identified a homozygous intronic mutation, c.2386-11A>G in BUB1B which creates a de novo splice site that is favored over the authentic site. This study expands the phenotype of BUB1B mutations and MVA to include common adult-onset cancers and provides evidence for the interdependency of APC and BUBR1 proteins in humans.
2010-06-09 | GSE22206 | GEO