STAT5BN642H is a driver mutation for T-cell neoplasia (RRBS)
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ABSTRACT:
PROVIDER: PRJNA413050 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6129053.fastq.gz | Fastqsanger.gz | |||
| SRR6129054.fastq.gz | Fastqsanger.gz | |||
| SRR6129055.fastq.gz | Fastqsanger.gz | |||
| SRR6129056.fastq.gz | Fastqsanger.gz | |||
| SRR6129057.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:STAT5BN642H is a driver mutation for T-cell neoplasia
| PRJNA413088 | 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:DNA methylation is a mechanism for long-term transcriptional regulation and is required for normal cellular differentiation. Failure to properly establish or maintain DNA methylation patterns leads to cell dysfunction and diseases such as cancer. Identifying DNA methylation signatures in complex tissues can be challenging due to inaccurate cell enrichment methods and low DNA yields. We have developed a technique called Laser Capture Microdissection-Reduced Representation Bisulfite Sequencing (LCM-RRBS) for the multiplexed interrogation of the DNA methylation status of CpG Islands and promoters. LCM-RRBS accurately and reproducibly profiles genome-wide methylation of DNA extracted from microdissected fresh frozen or formalin-fixed paraffin-embedded tissue samples. To demonstrate the utility of LCM-RRBS, we characterized changes in DNA methylation associated with gonadectomy-induced adrenocortical neoplasia in the mouse. Compared to adjacent normal tissue, the adrenocortical tumors showed reproducible gains and losses of DNA methylation at genes involved in cell differentiation and organ development. LCM-RRBS is a rapid, cost-effective, and sensitive technique for analyzing DNA methylation in heterogeneous tissues and will facilitate the investigation of DNA methylation in cancer and organ development. Laser capture microdissection-reduced representation bisulfite sequencing and reduced representation bisulfite sequencing on human blood leukocyte, human endometrial tumor, mouse liver tissue, and mouse normal and neoplastic adrenal tissue
2013-03-21 | E-GEOD-45361 | biostudies-arrayexpress
Project description:DNA methylation is a mechanism for long-term transcriptional regulation and is required for normal cellular differentiation. Failure to properly establish or maintain DNA methylation patterns leads to cell dysfunction and diseases such as cancer. Identifying DNA methylation signatures in complex tissues can be challenging due to inaccurate cell enrichment methods and low DNA yields. We have developed a technique called Laser Capture Microdissection-Reduced Representation Bisulfite Sequencing (LCM-RRBS) for the multiplexed interrogation of the DNA methylation status of CpG Islands and promoters. LCM-RRBS accurately and reproducibly profiles genome-wide methylation of DNA extracted from microdissected fresh frozen or formalin-fixed paraffin-embedded tissue samples. To demonstrate the utility of LCM-RRBS, we characterized changes in DNA methylation associated with gonadectomy-induced adrenocortical neoplasia in the mouse. Compared to adjacent normal tissue, the adrenocortical tumors showed reproducible gains and losses of DNA methylation at genes involved in cell differentiation and organ development. LCM-RRBS is a rapid, cost-effective, and sensitive technique for analyzing DNA methylation in heterogeneous tissues and will facilitate the investigation of DNA methylation in cancer and organ development.
2013-03-21 | GSE45361 | 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:A Dominant mutation in Dnmt1 leads epigenetic changes (rrbs)
| PRJNA715213 | ENA
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:BackgroundAll 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.MethodsWe 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.ResultsThe 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.ConclusionsOur 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: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