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XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor KPT-335.

ABSTRACT: The five-year survival rate remains less than 50% for high-risk neuroblastoma patients, few of them show effective response to current chemotherapy drugs. It is urgent to identify new therapeutic targets and corresponding drugs for high-risk neuroblastoma. Exportin-1(XPO1), also known as chromosomal region maintenance 1 (CRM1), plays important roles in the progress of tumorigenesis. However, the prognostic and therapeutic values of XPO1 in neuroblastoma have not been reported. Here, our results showed that overexpression of XPO1 was significantly associated with poor clinical characteristics and prognosis of neuroblastoma patients. The specific inhibitor of XPO1 suppressed neuroblastoma cell growth both in vitro and in vivo. Specifically, inhibition of XPO1 suppressed neuroblastoma cells proliferation and induced cell apoptosis by FOXO1 and RB1 nuclear accumulation in neuroblastoma through inhibiting PI3K/AKT pathway, and induced G0/G1 phase cell arrest by activating P53 function. Together, XPO1 is a promising prognostic indicator for neuroblastoma and a novel target for antitumor treatment by selective inhibitor verdinexor (KPT-335).

ORGANISM(S): Homo sapiens

PROVIDER: GSE163987 | GEO | 2021/08/18

REPOSITORIES: GEO

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XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor KPT-335.

Project description:XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor KPT-335.

| PRJNA688482 | ENA

High-throughput mRNA sequencing of CLL cells containing an E571K XPO1 mutations

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

Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias.

Project description: Not available

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XPO1 blockade with KPT-330 promotes apoptosis in Cutaneous T- cell Lymphoma by activating the p53-p21 and p27 pathways

Project description:To assess the effects of XPO1 inhibition with small molecule inhibitor KPT-330 on Cutaneous T-cell Lymphoma after 48 hours of treatment

2024-04-23 | GSE262491 | GEO

Genome-wide mapping of Nup98HoxA9- and Crm1-binding sites in ES cell lines.

Project description:We used ChIP-seq to examine the genome-wide binding of Nup98-HoxA9 and Crm1 in ES cells. Our analysis revealed that Nup98-HoxA9 is highly and preferentially targeted to specific chromatin sites, particularly near Hox cluster regions where the export factor Crm1 is originally prebound. chromatin immunoprecipitation

2016-01-04 | E-GEOD-68783 | biostudies-arrayexpress

Deep proteomic and phosphoproteomic profiling of neuroblastoma treated with XPO1 inhibitor Selinexor

Project description:Neuroblastoma accounts for 15% of cancer-related deaths in children, highlighting an unmet need for novel therapies. Selinexor is a small molecule inhibitor of XPO1 that shuffles cargo proteins with a nuclear export sequence, many of which are essential for cancer growth and cell maintenance, from the nucleus to the cytosol. We systematically tested the effect of selinexor against neuroblastoma cells in vitro and in vivo and used a proteomics screening approach to interrogate unknown mechanisms of action. We found that selinexor induces its cytotoxic effects in neuroblastoma through the nuclear accumulation of p53. By combining selinexor with an aurora kinase inhibitor, alisertib that is already in clinical use for neuroblastoma, we show that p53-mediated lethality can be further augmented supporting clinical testing of this drug combination against neuroblastoma

2023-03-11 | PXD026454 | Pride

XPO1 amplification abrogates the effects of E571K XPO1 mutation in B-cell lymphoma

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

Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276.

Project description: Not available

| S-EPMC3922416 | biostudies-literature

Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program.

Project description: Not available

| S-EPMC4722540 | biostudies-literature

Genome-wide mapping of Nup98HoxA9- and Crm1-binding sites in ES cell lines.

2016-01-04 | GSE68783 | GEO