Cancer -associated mutations in XPO1 transform cells through altered nuclear export signal recognition
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ABSTRACT:
PROVIDER: PRJNA492253 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7881960_1.fastq.gz | Fastqsanger.gz | |||
| SRR7881960_2.fastq.gz | Fastqsanger.gz | |||
| SRR7881970_1.fastq.gz | Fastqsanger.gz | |||
| SRR7881970_2.fastq.gz | Fastqsanger.gz | |||
| SRR7881961_1.fastq.gz | Fastqsanger.gz |
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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:Germline mutations in the transcriptional regulator ETV6 are a root cause of familial inherited thrombocytopenia and predispose carriers to myelodysplastic syndromes and acute leukemias. Here, we report that the ETV6 P214L mutation creates an XPO1-dependent nuclear export signal to cause protein mislocalization. Strategies to disrupt XPO1 nuclear export activity fully restore ETV6 P214L protein nuclear localization and transcription regulation activity, establishing XPO1-dependent mislocalization as a critical mechanism underscoring ETV6 P214L dysfunction. Mechanistic insight inspired the design of ‘humanized’ ETV6 mice in which the germline P214L mutation is sufficient to elicit severe defects in thrombopoiesis and hematopoietic stem cell maintenance and survival in animals. These studies define a unique mechanism by which the ETV6 P214L mutation exerts a dominant negative effect on protein function and reveal critical mutation-dependent disruptions to hematopoiesis that underlie disease phenotypes.
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Project description:Germline mutations in the transcriptional regulator ETV6 are a root cause of familial inherited thrombocytopenia and predispose carriers to myelodysplastic syndromes and acute leukemias. Here, we report that the ETV6 P214L mutation creates an XPO1-dependent nuclear export signal to cause protein mislocalization. Strategies to disrupt XPO1 nuclear export activity fully restore ETV6 P214L protein nuclear localization and transcription regulation activity, establishing XPO1-dependent mislocalization as a critical mechanism underscoring ETV6 P214L dysfunction. Mechanistic insight inspired the design of ‘humanized’ ETV6 mice in which the germline P214L mutation is sufficient to elicit severe defects in thrombopoiesis and hematopoietic stem cell maintenance and survival in animals. These studies define a unique mechanism by which the ETV6 P214L mutation exerts a dominant negative effect on protein function and reveal critical mutation-dependent disruptions to hematopoiesis that underlie disease phenotypes.
2025-04-11 | GSE288171 | GEO
Project description:UBTF tandem duplications (UBTF-TD) define a high-risk molecular subtype of acute myeloid leukemia (AML) characterized by poor clinical outcomes. While menin inhibitors have shown therapeutic promise, acquired resistance remains a significant challenge. Here, we use proteomic, genomic, and functional analyses to uncover mechanisms underlying UBTF-TD mediated leukemogenesis. We show that TDs create nuclear export signal (NES) motifs, which mediate interactions with Exportin-1 (XPO1) and chromatin-associated partners. These interactions drive aberrant chromatin binding and transcriptional activation of genes commonly dysregulated in UBTF-TD tumors, including the HOXA/HOXB clusters. We demonstrate that these NES motifs are critical for mislocalization of UBTF-TD proteins, cellular transformation, and transcriptional dysregulation. Importantly, we identify the XPO1 inhibitor eltanexor as a potential therapeutic strategy. Eltanexor treatment disrupts UBTF-TD chromatin localization, reduces tumor burden, and promotes differentiation in preclinical models. These findings provide mechanistic insights into UBTF-TD-driven leukemogenesis and highlight XPO1 inhibition as a promising therapy for UBTF-TD AMLs.
2025-10-01 | GSE290439 | GEO
Project description:UBTF tandem duplications (UBTF-TD) define a high-risk molecular subtype of acute myeloid leukemia (AML) characterized by poor clinical outcomes. While menin inhibitors have shown therapeutic promise, acquired resistance remains a significant challenge. Here, we use proteomic, genomic, and functional analyses to uncover mechanisms underlying UBTF-TD mediated leukemogenesis. We show that TDs create nuclear export signal (NES) motifs, which mediate interactions with Exportin-1 (XPO1) and chromatin-associated partners. These interactions drive aberrant chromatin binding and transcriptional activation of genes commonly dysregulated in UBTF-TD tumors, including the HOXA/HOXB clusters. We demonstrate that these NES motifs are critical for mislocalization of UBTF-TD proteins, cellular transformation, and transcriptional dysregulation. Importantly, we identify the XPO1 inhibitor eltanexor as a potential therapeutic strategy. Eltanexor treatment disrupts UBTF-TD chromatin localization, reduces tumor burden, and promotes differentiation in preclinical models. These findings provide mechanistic insights into UBTF-TD-driven leukemogenesis and highlight XPO1 inhibition as a promising therapy for UBTF-TD AMLs.
2025-10-01 | GSE290438 | GEO
Project description:UBTF tandem duplications (UBTF-TD) define a high-risk molecular subtype of acute myeloid leukemia (AML) characterized by poor clinical outcomes. While menin inhibitors have shown therapeutic promise, acquired resistance remains a significant challenge. Here, we use proteomic, genomic, and functional analyses to uncover mechanisms underlying UBTF-TD mediated leukemogenesis. We show that TDs create nuclear export signal (NES) motifs, which mediate interactions with Exportin-1 (XPO1) and chromatin-associated partners. These interactions drive aberrant chromatin binding and transcriptional activation of genes commonly dysregulated in UBTF-TD tumors, including the HOXA/HOXB clusters. We demonstrate that these NES motifs are critical for mislocalization of UBTF-TD proteins, cellular transformation, and transcriptional dysregulation. Importantly, we identify the XPO1 inhibitor eltanexor as a potential therapeutic strategy. Eltanexor treatment disrupts UBTF-TD chromatin localization, reduces tumor burden, and promotes differentiation in preclinical models. These findings provide mechanistic insights into UBTF-TD-driven leukemogenesis and highlight XPO1 inhibition as a promising therapy for UBTF-TD AMLs.
2025-10-01 | GSE290440 | GEO
Project description:XPO1 is a nuclear export protein that is frequently overexpressed in cancer and functions as a driver of oncogenesis. Currently small molecules that target XPO1 are being used in the clinic as anti-cancer agents. We identify XPO1 as a target for natural killer (NK) cells. Using immunopeptidomics we have identified a peptide derived from XPO1 that can be recognized by the activating NK cell receptor KIR2DS2 in the context of HLA-C. The peptide can be endogenously processed and presented to activate NK cells specifically through this receptor. Although high XPO1 expression in cancer is commonly associated with a poor prognosis, we show that the outcome of specific cancers, such as hepatocellular carcinoma, can be substantially improved if there is concomitant evidence of NK cell infiltration. We thus identify XPO1 as a bona fide tumor antigen recognised by NK cells, that offers an opportunity for a personalized approach to NK cell therapy for solid tumors.
2024-10-17 | PXD053264 | Pride
Project description:SF3B1 mutations are the most frequent spliceosomal alterations across cancers, yet no successful therapy exists to target this pathway. Previous findings from a phase 2 clinical trial of the XPO1 inhibitor selinexor in patients with high-risk myelodysplastic neoplasms (MDS) relapsed or refractory to hypomethylating agents (HMA) revealed increased activity in patients with SF3B1 mutations. XPO1 (Exportin-1) is responsible for the export of over 200 proteins, but also plays a role in the transport of multiple RNA species, including small nuclear RNAs (snRNAs), ribosomal RNAs (rRNAs), and select messenger RNAs (mRNAs) out of the nucleus. We therefore hypothesized that XPO1 inhibition perturbs RNA export and may preferentially affect SF3B1 mutants via altered splicing, given the role of XPO1 in exporting snRNAs, which form the catalytic portion of the spliceosome. To evaluate the mechanism underlying preferentially sensitivity of SF3B1-mutants to XPO1 inhibition, we performed nuclear and cytoplasmic fraction followed by RNA sequencing before and after XPO1 inhibition in SF3B1 wildtype and SF3B1 K666N cells (subcellular RNA-seq). Whole transcriptomic analysis of subcellular RNA-seq data revealed more nuclear retention of global RNA transcripts after XPO1 inhibition in the SF3B1 mutant cell line. Similarly, we performed subcellular RNA-seq for small RNAs and found snRNAs to be increased in the nucleus after XPO1 inhibition in the SF3B1 mutant cells. We then performed total cellular RNA sequencing to understand the effect of XPO1 inhibition on global RNA expression and RNA splicing. Differential gene expression analysis identified that XPO1 inhibition had the greatest effect on cell cycle in SF3B1 wildtype cells but in SF3B1-mutant cells differentiation pathways were more significantly affected. Alternative splicing analysis showed increased 3’ alternative splicing events in SF3B1 mutant after XPO1 inhibition. These results signify the mechanistic basis for preferential sensitivity of SF3B1 mutant cells to nuclear export inhibition arises through nuclear retention of spliceosomal snRNAs and select mRNAs that result in perturbation of differentiation pathways.
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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.
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Project description:The transcription factor GATA-3 and the transcriptional program it regulates have emerged as oncogenic drivers across diverse T-cell lymphomas (TCL), many of which are resistant to conventional chemotherapeutic agents and characterized by recurrent losses of key tumor suppressor genes, including TP53 and PTEN, both of which are clients of the nuclear export protein XPO1. Here we demonstrated that XPO1 is highly expressed by malignant T cells expressing GATA-3 and by lymphoma-associated macrophages (LAM) within their tumor microenvironment (TME). Using complementary genetically engineered mouse (GEM) models, we demonstrated that TP53 and/or PTEN deficient TCL, and LAM within their TME, are sensitive to the selective XPO1 antagonist selinexor. In an effort to identify TP53 and PTEN independent mechanisms, we used complementary and orthogonal approaches to investigate the role of eIF4e and XPO1-dependent mRNA nuclear export in these TCL. We identified a novel role for eIF4E/XPO1 in exporting GATA-3 and GATA-3-dependent transcripts from the nucleus in TCL, and in the export of therapeutically relevant transcripts, including CSF-1R, from LAM. Therefore, XPO1 antagonism, by impairing oncogenic transcriptional programs in TCL and depleting LAM from their TME, is a novel approach to target two independent dependencies in a group of therapeutically challenging TCL.
2024-12-31 | GSE267408 | GEO