High-throughput mRNA sequencing of CLL cells containing an E571K XPO1 mutations
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PROVIDER: PRJNA685838 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: Exportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood. Thus, we aimed to identify disrupted cellular pathways in response to the E571K XPO1 mutation, the mutation most frequently cited in CLL patients, via high-throughput RNA-sequencing Results & Conclusion: Multidimensional scaling (MDS) analysis of the top 1000 most variable genes demonstrated distinctly unique clustering along the first dimension for XPO1-E571K patient and XPO1-wt patient samples. This clustering pattern was driven by a number of genes that were either over- or under-expressed in XPO1-E571K patient cells, contributing to a unique gene expression pattern in patients with this mutation signature.
2021-01-21 | GSE163370 | GEO
Project description:Proper nucleocytoplasmic distribution of proteins is essential to cellular homeostasis but what role the altered nuclear export machinery commonly described in cancer cells plays in cancer initiation is not known. Here, genomic analysis of 42,793 cancers identified recurrent mutational hotspots in XPO1, the main nuclear export receptor in eukaryotic cells. Expression of XPO1 mutations in vivo was sufficient to initiate clonal, B-lymphoproliferative disorders by altering the constellation of proteins exported from the nucleus based on amino acid charge C-terminal to their nuclear export signal. Impaired export of one such protein, the NFkB inhibitor IB enhanced NFkB signaling, a pathway frequently activated by somatic mutations in cancers enriched in XPO1 mutations. These data identify change-of-function mutations in nuclear export as novel drivers of tumorigenesis.
2021-09-01 | GSE120231 | GEO
Project description:Chronic Lymphocytic Leukemia (CLL) is a heterogeneous disease with a variable clinical course strictly dependent on cytogenetic and molecular features. However, in 15-20% of cases both conventional cytogenetic and FISH analyses do not show any kind of abnormality. With the aim to identify dependable molecular prognostic factors in this subgroup, we evaluated 171 CLL patients, without aberrations detected by chromosome banding and FISH analysis. A comprehensive analysis was performed including genomic arrays (CGH+SNP), IGHV status, flow cytometry and a targeted sequencing. By genomic arrays, we detected 73 aberrations in 39 patients (23%). Most frequently, patients had 1 aberration (25/171; 15%), while 14 patients (8%) had at least 2 aberrations. IGHV unmutated status was present in 53/171 (31%) patients. SF3B1 was the most frequently mutated gene (26/171 patients; 15%), followed by NOTCH1 (n=15, 9%), ATM (n=5; 3%); TP53 (n=5; 3%); KLHL6 (n=5; 3%); MYD88 (n=5; 3%) and XPO1 (n=5; 3%). At univariate analysis, an adverse impact on time to treatment (TTT) was evident for SF3B1 mutations, higher white blood cell count, higher CLL cells percentage by flow cytometry, CD38 positivity, IGHV unmutated status and at least 2 genomic array abnormalities. Of them, SF3B1 mutations, CLL cells percentage, IGHV unmutated status and number of genomic array aberrations maintained their impact in multivariate analysis. In conclusion, integrating genomic and molecular data, we identified patients at higher risk for treatment need. Therefore, we suggest to evaluate these factors for a better prognostic stratification of normal karyotype CLL subset.
2017-08-31 | GSE103306 | GEO
Project description:XPO1 gene encodes exportin 1 (XPO1) that controls the nuclear export of cargo proteins and RNAs. Almost 25% of primary mediastinal B-cell lymphomas (PMBL) and classical Hodgkin lymphomas (cHL) cases harboured a recurrent XPO1 point mutation (NM_003400, chr2:g61718472C>T) resulting in the E571K modification within the hydrophobic groove of the protein, the site of cargo proteins binding. We investigated the functional impact of XPO1E571K mutation using cell lines having various XPO1 status. We first confirmed that the mutation was present both within the XPO1 mRNA and the corresponding protein. In the U2940 cell line having a wild-type (wt) XPO1 gene, we introduced the E571K mutation using several CRISPR-Cas9 strategies. Using a barcoding method to trace the mutation, we observed that the mutation gave no advantage in vitro. Indeed, the effects of XPO1E571K mutation were hidden by the presence of the XPO1 wt allele. Strikingly, XPO1E571K mutation never occurred as homozygous or hemizygous in our patients��������� cohort. We further showed that XPO1E571K mutation modified selinexor binding to XPO1 and in turn, its sensitivity to this drug. We concluded that the balance between the wild-type and the mutated allele of XPO1 is a key element in defining XPO1 functions and oncogenic properties.
2020-10-01 | PXD016916 | Pride
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:Cancer -associated mutations in XPO1 transform cells through altered nuclear export signal recognition
| PRJNA492253 | ENA
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:We performed genome-wide methylation profiling of CLL in an Asian cohort for the first time. Eight Korean patients without somatic immunoglobulin heavy chain gene hypermutations underwent methyl-CpG binding domain sequencing (MBD-seq), as did five control subjects. Gene Ontology, pathway analysis, and network-based prioritization of differentially methylated genes were also performed. We found more hypomethylated regions (2,062 windows) than hypermethylated regions (777 windows). Promoters contained the highest proportion of differentially methylated regions (DMRs; approximately 0.08%), while distal intergenic and intron regions contained the largest number of DMRs. Protein-coding genes were the most abundant, followed by long noncoding and short noncoding genes. The most significantly dysregulated signaling pathways included immune/cancer-related pathways and B-cell receptor signaling. Among the top 10 hub genes identified via network-based prioritization, four novel candidate genes (UBC, GRB2, CREBBP, and GAB2) had no known relevance to CLL while the other six (STAT3, PTPN6, SYK, STAT5B, XPO1, and ABL1) have previously been linked to CLL in Caucasians. As such, our analysis identified four novel candidate genes of potential significance to Asian patients with CLL.
2020-02-03 | GSE136986 | GEO
Project description:Background: p53 plays a key role in determining the clinical features of B cell chronic lymphocytic leukemia (CLL). Disruption of p53 by point mutations, deletion at 17p13, or both, occurs in a fraction of cases at diagnosis and predicts poor survival and chemorefractoriness. In cells with functional p53, p53 activity is inhibited through interaction with MDM2. In fact, p53 can be activated upon exposure of cells to inhibitors of p53/MDM2 interaction, like Nutlins. Exposure of CLL cells to Nutlin-3 is effective in raising the levels of p53 protein with subsequent induction of cell cycle arrest and/or apoptosis, independently of the most relevant prognostic markers. Specific gene-sets and GEP were documented to be associated with response or resistance to Nutlin-3 exposure in p53(wt) or p53(del/mut) CLL. These findings may help to identify novel molecular targets for CLL therapy. Aim: to analyze the gene expression profile (GEP) induced by Nutlin-3 exposure in primary CLL cells from p53(wt) and p53(del/mut) cases. Methods: purified cells from 24 PB CLL samples, all characterized for IGHV mutational status, CD38 and ZAP-70 and p53 mutations (16 p53(wt) CLL, 8 p53(del/mut) CLL of which 6 with del17p13 and p53 mutations, 1 with del17p13 alone, and 1 with p53 mutations alone), were exposed to 10 uM Nutlin-3 for 24 hours. GEP was performed using a dual labelling strategy; the differential expression of the below reported genes were validated by quantitative real-time PCR. specific gene-sets and GEP were documented to be associated with response or resistance to Nutlin-3 exposure in p53(wt) or p53(del/mut) CLL. These findings may help to identify novel molecular targets for CLL therapy.
2009-11-11 | GSE18971 | 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