Similar Datasets
Project description:The pathogenesis of many rare tumor types is poorly understood, preventing the design of effective treatments. Solitary Fibrous Tumors (SFTs) are neoplasms of mesenchymal origin that affect 1/1,000,000 individuals every year and are clinically assimilated to sarcomas. SFTs are commonly found throughout the body and can be surgically removed upon diagnosis. However, 30-40% of tumors become aggressive and can locally relapse or metastasize. There are no effective treatments for malignant SFTs to date. The molecular hallmark of SFTs is a gene fusion between the NAB2 and STAT6 loci on chromosome 12, resulting in a chimeric protein of poorly characterized function called NAB2-STAT6. We use primary samples and an inducible cell model to discover that NAB2-STAT6 operates as a transcriptional coactivator for a specific set of enhancers and promoters that are normally targeted by the EGR1 transcription factor. In physiological conditions, NAB2 is primarily localized to the cytoplasm and only a small nuclear fraction is available to operate as a co-activator of EGR1 targets. NAB2-STAT6 redirects NAB1, NAB2, and additional EGR1 to the nucleus and bolster the expression of neuronal EGR1 targets. The STAT6 moiety of the fusion protein is a major driver of its nuclear localization and further contributes to NAB2’s co-activating abilities. In primary tumors, NAB2-STAT6 activates a neuroendocrine gene signature that sets it apart from most sarcomas. These discoveries provide new insight into the pathogenesis of SFTs and reveal new targets with therapeutic potential.
2024-05-01 | GSE249700 | GEO
Project description:The pathogenesis of many rare tumor types is poorly understood, preventing the design of effective treatments. Solitary Fibrous Tumors (SFTs) are neoplasms of mesenchymal origin that affect 1/1,000,000 individuals every year and are clinically assimilated to sarcomas. SFTs are commonly found throughout the body and can be surgically removed upon diagnosis. However, 30-40% of tumors become aggressive and can locally relapse or metastasize. There are no effective treatments for malignant SFTs to date. The molecular hallmark of SFTs is a gene fusion between the NAB2 and STAT6 loci on chromosome 12, resulting in a chimeric protein of poorly characterized function called NAB2-STAT6. We use primary samples and an inducible cell model to discover that NAB2-STAT6 operates as a transcriptional coactivator for a specific set of enhancers and promoters that are normally targeted by the EGR1 transcription factor. In physiological conditions, NAB2 is primarily localized to the cytoplasm and only a small nuclear fraction is available to operate as a co-activator of EGR1 targets. NAB2-STAT6 redirects NAB1, NAB2, and additional EGR1 to the nucleus and bolster the expression of neuronal EGR1 targets. The STAT6 moiety of the fusion protein is a major driver of its nuclear localization and further contributes to NAB2’s co-activating abilities. In primary tumors, NAB2-STAT6 activates a neuroendocrine gene signature that sets it apart from most sarcomas. These discoveries provide new insight into the pathogenesis of SFTs and reveal new targets with therapeutic potential.
2024-05-01 | GSE249702 | GEO
Project description:The pathogenesis of many rare tumor types is poorly understood, preventing the design of effective treatments. Solitary Fibrous Tumors (SFTs) are neoplasms of mesenchymal origin that affect 1/1,000,000 individuals every year and are clinically assimilated to sarcomas. SFTs are commonly found throughout the body and can be surgically removed upon diagnosis. However, 30-40% of tumors become aggressive and can locally relapse or metastasize. There are no effective treatments for malignant SFTs to date. The molecular hallmark of SFTs is a gene fusion between the NAB2 and STAT6 loci on chromosome 12, resulting in a chimeric protein of poorly characterized function called NAB2-STAT6. We use primary samples and an inducible cell model to discover that NAB2-STAT6 operates as a transcriptional coactivator for a specific set of enhancers and promoters that are normally targeted by the EGR1 transcription factor. In physiological conditions, NAB2 is primarily localized to the cytoplasm and only a small nuclear fraction is available to operate as a co-activator of EGR1 targets. NAB2-STAT6 redirects NAB1, NAB2, and additional EGR1 to the nucleus and bolster the expression of neuronal EGR1 targets. The STAT6 moiety of the fusion protein is a major driver of its nuclear localization and further contributes to NAB2’s co-activating abilities. In primary tumors, NAB2-STAT6 activates a neuroendocrine gene signature that sets it apart from most sarcomas. These discoveries provide new insight into the pathogenesis of SFTs and reveal new targets with therapeutic potential.
2024-05-01 | GSE249701 | GEO
Project description:NAB2-STAT6 drives an EGR1-dependent neuroendocrine program in Solitary Fibrous Tumors
| PRJNA1050208 | ENA
Project description:NAB2-STAT6 drives an EGR1-dependent neuroendocrine program in Solitary Fibrous Tumors (ChIP-Seq)
| PRJNA1050212 | ENA
Project description:NAB2-STAT6 drives an EGR1-dependent neuroendocrine program in Solitary Fibrous Tumors (RNA-Seq)
| PRJNA1050217 | ENA
Project description:NAB2-STAT6 drives an EGR1-dependent neuroendocrine program in Solitary Fibrous Tumors (ATAC-Seq)
| PRJNA1050213 | ENA
Project description:Solitary fibrous tumors (SFTs) are rare mesenchymal tumors. Here, we describe the identification of a NAB2-STAT6 fusion from whole-exome sequencing of 17 SFTs. Analysis in 53 tumors confirmed the presence of 7 variants of this fusion transcript in 29 tumors (55%), representing a lower bound for fusion frequency at this locus and suggesting that the NAB2-STAT6 fusion is a distinct molecular feature of SFTs.
| S-EPMC3984043 | biostudies-literature
Project description:NAB2-STAT6 gene fusion drives STAT6 nuclear expression and is the pathognomonic hallmark of solitary fibrous tumors (SFTs). However, no study has systematically analyzed the clinicopathological features, STAT6 immunoexpression status, or the fusion variants of NAB2-STAT6 in intrathoracic SFTs. Fifty-two intrathoracic SFTs were retrieved to appraise histopathology, assess STAT6 immunoexpression, and determine NAB2-STAT6 fusion variants by RT-PCR. Location-relevant histologic mimics served as controls. Thirty-one pleura-based, 12 mediastinal/pericardial, and nine intrapulmonary lesions were histologically categorized into eight malignant, eight atypical, and 36 conventional or cellular SFTs, including two fat-forming and two giant cell angiofibroma-like SFTs. STAT6 distinctively decorated the tumoral nuclei in 51 (98%) SFTs. However, no nuclear staining was observed in the histological mimics. NAB2-STAT6 fusion was detected in 34 SFTs. Twenty-nine (85.3%) exhibited the major NAB2ex4-STAT6ex2/3 variant and 5 (14.7%) the minor NAB2ex6-STAT6ex16/17. NAB2ex4-STAT6ex2 was significantly associated with older age (P = 0.01) and pleuropulmonary tumors (P = 0.025). After a median follow-up of 33.9 (range, 0.3-174.6) months, adverse outcomes occurred in one atypical and five malignant SFTs, including two local relapses, one intrapulmonary metastasis, and three extrathoracic metastases. Inferior disease-free survival was univariately associated with atypical/malignant histology (P = 0.001) and a mitosis >4/10 HPFs (P = 0.0012) but was unrelated to fusion variants. In conclusion, the majority of intrathoracic SFTs exhibited STAT6 nuclear staining, and NAB2ex4-STAT6ex2/3 was the predominant fusion type. However, clinical aggressiveness is associated with atypical/malignant histology primarily contributed by increased mitosis but was unrelated to the NAB2-STAT6 fusion variants.
| S-EPMC4735766 | biostudies-literature
Project description:A 44-year old woman with recurrent solitary fibrous tumor (SFT)/hemangiopericytoma was enrolled in a clinical sequencing program including whole-exome and transcriptome sequencing. A gene fusion of the transcriptional repressor NAB2 with the transcriptional activator STAT6 was detected. Transcriptome sequencing of 27 additional SFTs identified the presence of a NAB2-STAT6 gene fusion in all tumors. Using RT-PCR and sequencing, we detected this fusion in all 51 SFTs, indicating high levels of recurrence. Expression of NAB2-STAT6 fusion proteins was confirmed in SFT, and the predicted fusion products harbor the early growth response (EGR)-binding domain of NAB2 fused to the activation domain of STAT6. Overexpression of the NAB2-STAT6 gene fusion induced proliferation in cultured cells and activated the expression of EGR-responsive genes. These studies establish NAB2-STAT6 as the defining driver mutation of SFT and provide an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator.
| S-EPMC3654808 | biostudies-literature