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Mutant SF3B1 promotes AKT and NF-kB driven mammary tumorigenesis

ABSTRACT: Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma, but also recurrent in epithelial malignancies such as breast cancer. Whereas hotspot mutations in SF3B1 alter hematopoietic differentiation, whether SF3B1 mutations contribute to epithelial cancer development and progression is unknown. Here, we identify that SF3B1 mutations in mammary epithelial and breast cancer cells induce a recurrent pattern of aberrant splicing leading to activation of AKT and NF-kB, enhanced cell migration, and accelerated tumorigenesis. Transcriptomic analysis of human cancer specimens, MMTV-cre Sf3b1K700E/WT mice, and isogenic mutant cell lines identified hundreds of aberrant 3’ splice sites induced by mutant SF3B1, a portion of which were breast-specific. Across mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the aberrant branchpoint) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-kB. Coordinate activation of NF-kB and AKT signaling was observed in the knock-in models, leading to accelerated cell migration and tumor development in combination with mutant PIK3CA but also hypersensitizing cells to AKT kinase inhibitors. These data identify mutations in SF3B1 as drivers of breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE145471 | GEO | 2021/01/05

REPOSITORIES: GEO

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GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies

Project description:Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, but therapeutic means to correct this mis-splicing do not exist. Here, we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain-containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SUGP1, a G-patch protein recently implicated in SF3B1-mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1-dependent splicing defects and was sufficient to improve dysfunctional hematopoiesis in SF3B1-mutant mouse and primary human progenitors. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and highlight the therapeutic impact of correcting aberrant splicing in SF3B1-mutant cancers.

2024-04-10 | PXD051128 | Pride

Mutant SF3B1 promotes AKT and NF-kB driven mammary tumorigenesis

Project description:Mutant SF3B1 promotes AKT and NF-kB driven mammary tumorigenesis

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Cancer associated SF3B1 hotspot mutations induce cryptic 3' splice site selection through use of a different branch point

Project description:Recurrent mutations in the spliceosome are observed in several human cancers but their functional and therapeutic significance remain elusive. SF3B1, the most frequently mutated component of the spliceosome in cancer, is involved in the recognition of the branch point sequence (BPS) during selection of the 3’ splice site (ss) in RNA splicing. Here, we report that common and tumor-specific splicing aberrations are induced by SF3B1 mutations and establish aberrant 3’ ss selection as the most frequent splicing defect. Strikingly, mutant SF3B1 utilizes a BPS that differs from that used by wild-type SF3B1 and requires the canonical 3’ ss to enable aberrant splicing during the second step. Approximately 50% of the aberrantly spliced mRNAs are subjected to nonsense-mediated decay resulting in downregulation of gene and protein expression. These findings ascribe functional significance to the consequences of SF3B1 mutations in cancer. 72 samples, including two sets of patient data and cell lines with two additional technical replicates each

2015-09-08 | E-GEOD-72790 | biostudies-arrayexpress

Synthetic Introns Identify GPATCH8 as Required for Mis-splicing by SF3B1 Mutations [RNA-Seq 2]

Project description:Mutations in the RNA splicing factor SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing but therapeutic means to correct this mis-splicing do not exist. Here we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SUGP1, a G-patch protein recently implicated in SF3B1 mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1 splicing defects and was sufficient to improve hematopoiesis in SF3B1 mutant mouse and human cells. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and the therapeutic impact of correcting aberrant splicing in SF3B1 mutant cancers.

2024-03-20 | GSE262021 | GEO

Synthetic Introns Identify GPATCH8 as Required for Mis-splicing by SF3B1 Mutations [TRIBE-seq]

2023-09-01 | GSE242093 | GEO

Synthetic Introns Identify GPATCH8 as Required for Mis-splicing by SF3B1 Mutations [RNA-seq]

2023-09-01 | GSE242092 | GEO

Spliceosomal disruption of the non-canonical BAF complex in cancer

Project description:SF3B1 is the most commonly mutated RNA splicing factor in cancer, but the mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here, we integrated pan-cancer RNA sequencing to identify mutant SF3B1-dependent aberrant splicing with a positive enrichment CRISPR screen to prioritize splicing alterations that functionally promote tumorigenesis. We identify that diverse, recurrent SF3B1 mutations converge on repression of BRD9, a core component of the recently described non-canonical BAF (ncBAF) complex. Mutant SF3B1 recognizes an aberrant deep intronic branchpoint within BRD9, thereby inducing inclusion of an endogenous retrovirus-derived poison exon and BRD9 mRNA degradation. BRD9 depletion causes loss of ncBAF at CTCF-bound loci and promotes melanomagenesis. We demonstrate that BRD9 is a potent tumor suppressor in uveal melanoma, such that correcting BRD9 mis-splicing in SF3B1-mutant cell lines and patient-derived melanoma xenografts with antisense oligonucleotides (ASOs) or by directly targeting its poison exon with CRISPR-directed mutagenesis profoundly suppresses tumor growth. Our results implicate disruption of ncBAF in the diverse malignancies characterized by SF3B1 mutations, identify a single aberrant splicing event which functionally contributes to the pathogenesis of SF3B1-mutant cancers, and suggest a mechanism-based therapeutic for these malignancies.

2019-06-19 | GSE124720 | GEO

Transcriptomic analyses of primary uveal melanomas

Project description:SF3B1 is coding an essential splicing factor. This gene was found recurrently mutated in uveal melanoma. To understand the consequences of these hotspot SF3B1 mutations, we performed high coverage RNA-seq on 74 primary uveal melanomas, which were treated by primary enucleation. We analyzed data for aberrant splicing in relation with SF3B1 status.

2016-07-03 | E-MTAB-4097 | biostudies-arrayexpress

Novel SF3B1 Deletion Mutations Result in Aberrant RNA Splicing in CLL Patients

Project description:Recurrent mutations in RNA splicing factors SF3B1, U2AF1, and SRSF2 have been reported in hematologic cancers including myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL). However, SF3B1 is the only splicing associated gene to be found mutated in CLL and has been shown to induce aberrant splicing. To investigate if any other genomic aberration caused similar transcriptome changes, we clustered RNASeq samples based on an alternative 3’ splice site (ss) pattern previously identified in SF3B1-mutant CLL patients. Out of 215 samples, we identified 37 (17%) with alternative 3’ ss usage, the majority of which harbored known SF3B1 hotspot mutations. Interestingly, 3 patient samples carried previously unreported in-frame deletions in SF3B1 around K700, the most frequent mutation hotspot. To study the functional effects of these deletions, we used various minigenes demonstrating that recognition of canonical 3’ ss and alternative branchsite are required for aberrant splicing, as observed for SF3B1 p.K700E. The common mechanism of action of these deletions and substitutions result in similar sensitivity of primary cells towards splicing inhibitor E7107. Altogether, these data demonstrate that novel SF3B1 in-frame deletion events identified in CLL result in aberrant splicing, a common biomarker in spliceosome-mutant cancers.

2017-06-27 | GSE95352 | GEO

Synthetic lethal interactions and convergent biological effects underlie the mutual exclusivity of MDS-associated spliceosomal gene mutations

Project description:RNA splicing factor mutations constitute the most common class of alterations in myelodysplastic syndromes (MDS). These occur as heterozygous mutations at restricted residues in SF3B1, SRSF2, and U2AF1 in a mutually exclusive manner. The mutual exclusivity of spliceosomal mutations suggests synthetic lethal and/or convergent biological effects of these mutations; however, there is currently no functional evidence supporting either of these possibilities. Here we report that spliceosomal mutations, despite imparting distinct alterations on gene expression and splicing, are negatively selected for when co-expressed in the same cell or in a homozygous state. Co-expression of these mutations results in additive, rather than synergistic, effects on RNA splicing mechanisms. Despite disparate global effects on splicing, aberrant splicing of distinct kinases by mutant SF3B1 and SRSF2 results in hyperactivated NF-κB signaling. These data identify convergent biological consequences of splicing factor mutations and the functional basis for the mutual exclusivity and heterozygous nature of these mutations.

2018-08-13 | GSE97452 | GEO

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