Gene expression study in SF3B1-mutated, NOTCH1-mutated and WT CLL cells
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PROVIDER: PRJNA564296 | ENA |
REPOSITORIES: ENA
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Project description:Mutations of SF3B1 in CLL induce alternative splicing in multiple transcripts, including DVL2. DVL2 in turn can act as a negative regulator of NOTCH1 signaling. Gene Expression Profile (GEP) was used to investigate the activation of the NOTCH1 pathway in presence of alternatively spliced DVL2.
2019-09-07 | GSE137024 | GEO
Project description:Stabilizing mutations of NOTCH1 have been identified in about 10% of chronic lymphocytic leukemia (CLL) cases at diagnosis, with a higher frequency in unmutated IGHV (IGHV-UM) CLL, chemorefractory CLL and CLL in advanced disease phases. Clinically, the presence of NOTCH1 mutations is an independent predictor of overall survival in CLL and associates with resistance to anti-Cd20 immunotherapy. The Gene Expression Profile was generated to identify the peculiar molecular signatures of NOTCH1 mutated CLL in the context of IGHV-UM CLL.
2016-03-01 | GSE75122 | GEO
Project description:Stabilizing mutations of NOTCH1 have been identified in about 10% of chronic lymphocytic leukemia (CLL) cases at diagnosis, with a higher frequency in unmutated IGHV (IGHV-UM) CLL, chemorefractory CLL and CLL in advanced disease phases. Clinically, the presence of NOTCH1 mutations is an independent predictor of overall survival in CLL and associates with resistance to anti-Cd20 immunotherapy. The Gene Expression Profile was generated to identify the peculiar molecular signatures of NOTCH1 mutated CLL in the context of IGHV-UM CLL. Constitutive gene expression in CLL cells bearing or not NOTCH1 mutation (c.7541_7542delCT). Five samples were selected for each category (WT vs MUT).
2016-03-01 | E-GEOD-75122 | biostudies-arrayexpress
Project description:In CLL, NOTCH1 is the most commonly mutated gene at diagnosis and it is associated with a poor outcome. The mechanisms underlying how NOTCH1 contributes to disease progression, resistance to treatment and Richter’s transformation remain largely unknown. The main goal of this study is to compare the gene expression profile of primary CLL cells transduced with the intracellular part of NOTCH1 lacking of the PEST domain vs cells transduced with an empty vector. Additionally, patients with the Trisomy 12 abnormality are included in this study to clarify the role of the mutations in this specific sub-group of CLL patients that are strongly associated with NOTCH1 mutations.
2022-09-08 | GSE150584 | GEO
Project description:In CLL, NOTCH1 is the most commonly mutated gene at diagnosis and it is associated with a poor outcome. The mechanisms underlying how NOTCH1 contributes to disease progression, resistance to treatment and Richter’s transformation remain largely unknown. Data suggests a link between BCR activation and NOTCH1 signalling so the main goal of this study is to compare the gene expression profile of primary CLL cells transduced with the intracellular part of NOTCH1 lacking of the PEST domain vs cells transduced with an empty vector following IgM stimulation.
2022-09-08 | GSE150595 | GEO
Project description:In chronic lymphocytic leukemia (CLL), NOTCH1 is the most commonly mutated gene at diagnosis and it is associated with a poor outcome. The mechanisms underlying how NOTCH1 contributes to disease progression, resistance to treatment and Richter’s transformation remain largely unknown. The main goal of this study is to compare the chromatin activation profile of primary CLL cells transduced with the intracellular part of NOTCH1 lacking of the PEST domain vs. cells transduced with an empty vector. Additionally, patients with the Trisomy 12 abnormality are included in this study to clarify the role of the mutations in this specific sub-group of CLL patients that are strongly associated with NOTCH1 mutations.
2022-09-08 | GSE166727 | GEO
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
Project description:The RNA splicing factor SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its functional role in the pathogenesis of this disease has not been firmly established. Here, we show that conditional expression of heterozygous Sf3b1-K700E mutation in mouse B lineage cells disrupts pre-mRNA splicing, alters B-cell development and function, and induces a state of cellular senescence. B-cell restricted expression of this mutation combined with Atm deletion led to the overcoming of cellular senescence, together with enhanced genome instability and the development of clonal B220+CD5+ CLL cells in elderly mice at low penetrance. Mice with CLL-like disease were found to have amplifications of chromosomes 15 and 17. Integrated transcriptome and proteome analysis of the CLL-like cells revealed coordinated dysregulation of multiple CLL-associated cellular processes. This included an unexpected signature of deregulated B-cell receptor (BCR) signaling, which we could also identify in SF3B1-mutated CLL samples from two independent patient cohorts. Notably, human CLLs harboring SF3B1 mutations exhibited greater sensitivity and altered response kinetics to BTK kinase ibrutinib. Our genetically faithful murine model of CLL thus reveals fresh insights regarding the impact of SF3B1 mutation on CLL pathogenesis and suggests a system for identifying vulnerabilities related to this mutation that can be further exploited for the treatment of CLLs with this common mutation.
2018-11-20 | GSE122668 | GEO
Project description:Alternative splicing plays a critical role in generating transcriptome diversity, and aberrant splicing is frequently observed in cancer. Mutations in the splicing factor SF3B1 are particularly common in patients with chronic lymphocytic leukemia (CLL) and myelodysplastic syndromes (MDS), with different survival prognoses. We applied long-read sequencing for the investigation of the SF3B1 mutation effect on the transcriptome of MDS and CLL patients, as well as isogenic cell lines. Our results revealed that SF3B1 mutation effect was common across the different diseases and specifically altered the usage of 3’ alternative splice sites within short proximity to the canonical splice sites. Based on computational simulations, the most common K700E mutation led to destabilization of the SF3B1-mRNA binding. Furthermore, we combined the full isoform information with genome-wide SF3B1-RNA binding maps to predict the functional consequences of the aberrant splicing and gain mechanistic insights into the role of mutated SF3B1 in splicing.
2024-08-19 | GSE247658 | GEO
Project description:Gene expression profile of primary CLL cells transduced with a mutated NOTCH1
| PRJNA632904 | ENA