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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163370 | GEO | 2021/01/21

REPOSITORIES: GEO

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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

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

Project description: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).

2021-08-18 | GSE163987 | GEO

Prolonged XPO1 inhibition is essential to achieve optimal antileukemic activity in NPM1-mutated acute myeloid leukemia

Project description:NPM1-mutated acute myeloid leukemia (AML) accounts for one third of AML in adults. NPM1-mutated AML maintenance depends on the interaction between mutated NPM1 (NPM1c) and the nuclear exporter Exportin 1 (XPO1). In this work, we show that continous XPO1 inhibition is necessary to achieve stable disruption of the NPM1c-XPO1 interaction and to induce HOX downregulation and differentiation of AML cells with mutated NPM1. In contrast, intermittent XPO1 inhibition only results in minimal transcriptional perturbation and limited antileukemic activity.

2022-09-21 | GSE181176 | GEO

Stk38 interactomics by proximity ligation

Project description:STK38 (aka NDR1) is a Hippo pathway serine/threonine protein kinase with multifarious functions in normal and cancer cells. Using a context-dependent proximity labelling assay, we discovered that STK38 modulates its interaction with more than 250 proteins depending on the context. Upon starvation-induced autophagy, STK38 associates with cytoplasmic proteins while upon ECM detachment it binds to mainly nuclear proteins. This differential subcellular-localization-dependent activity is caused by the XPO1 (Exportin-1, CRM1) dependent nuclear/cytoplasmic shuttling of STK38. STK38 associates with nuclear related partners upon ECM detachment and with cytoplasmic related ones upon autophagy, exhibiting a nuclear/cytoplasmic shuttling under the dependency of XPO1 (Exportin-1, aka CRM1). We further uncovered that the XPO1-mediated export of STK38 is dependent on phosphorylation of XPO1s serin residue 1055 by STK38 itself. In addition to regulating its own nuclear export, STK38 also controls the subcellular distribution of Beclin1, a key regulator of autophagy. Moreover, the regulation of XPO1 by STK38 mediates the nuclear exclusion of YAP1. Collectively, our results reveal that functions of STK38 are linked to the XPO1-mediated subcellular distribution of STK38 and key regulators. These observations show that unrelated cellular functions can be regulated by a same mechanism controlled by a single kinase and demonstrate a novel mechanism of XPO1-dependent cargo export regulation y phosphorylation of XPO1s C-terminal auto-inhibitory domain.

2019-09-26 | PXD011968 | Pride

CRISPR-Cas9 screening of KSHV-transformed cells identifies XPO1 as a vulnerable target of cancer cells by inducing p62 SQSTM1-mediated p53 activation in PML bodies

Project description:Mislocalization of oncogenes and tumor suppressors resulting from aberrant nuclear export promotes uncontrolled cell proliferation and growth transformation of cancer cells. We performed a genome-wide CRISPR-Cas9 screening in matched primary and KSHV-transformed cells, and identified genes that were pro-growth and growth-suppressive of both types of cells, of which exportin XPO1 was a critical factor for the survival of transformed cells. Using XPO1 inhibitor KPT-8602 and by siRNA-mediated knockdown, we confirmed the essential role of XPO1 in cell proliferation and growth transformation of KSHV-transformed cells, as well as cell lines of other types of cancer including gastric cancer and liver cancer. XPO1 inhibition induced cell cycle arrest and p53 activation, which depended on the formation of PML nuclear bodies. Furthermore, XPO1 induced relocalization of autophagy adaptor protein p62 (SQSTM1), recruiting p53 for activation in PML nuclear bodies. Our findings highlight a novel mechanism of p53 activation and identify XPO1 as a vulnerable target of cancer cells.

2019-05-21 | GSE125507 | GEO

Gene expression profiling of human DLD-1 cells after block of CRM1 receptor with Leptomycin B inhibitor.

Project description:We used RNA-seq approach to define a contribution of mammalian export receptor CRM1 (Chromosomal Maintenance 1 or Exportin 1) into Tpr-dependent export of RNA molecules from the nucleus to the cytoplasm. Basket nucleoporin Tpr was AID-tagged and depleted through Auxin Induced Degradation system. Loss of Tpr led to rapid changes in gene expression profile, and gene expression changes were compared to GANP, NXF1, RanGAP1 (GSE132363) and CRM1 loss and inhibition, respectively. Altogether, we found a minimal subset of RNAs that are controlled both by Tpr nucleoporin and CRM1 receptor.

2020-06-15 | GSE148560 | GEO

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

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

| PRJNA685838 | ENA

XPO1 is a critical player for Bortezomib resistance in Multiple Myeloma: A quantitative proteomic approach

Project description:Among the blood cancers, 13% mortality is caused by Multiple myeloma (MM) type of haematological malignancy. In spite of therapeutic advances in chemotherapy treatment, still MM remains an incurable disease is mainly due to emergence of chemoresistance. At present time, FDA approved bortezomib is the first line drug for MM treatment. However, like other chemotherapy, MM patients are acquiring resistance against bortezomib. The present study aims to identify and validate bortezomib resistant protein targets in MM using iTRAQ and label free quantitative proteomic approaches. 125 differentially expressed proteins were commonly found in both approaches with similar differential expression pattern. XPO1 protein was selected for further validation as its significant high expression was observed in both iTRAQ and label free analysis. Bioinformatic analysis of these common differentially expressed proteins showed a clear cluster of proteins such as SMC1A, RCC2, CSE1, NUP88, NUP50, TPR, HSPA14, DYNLL1, RAD21 and RANBP2 being associated with XPO1. Functional studies like cell count assay, flow cytometry assay and soft agar assay proved that XPO1 knock down in RPMI 8226R cell line results in re-sensitization to bortezomib drug

2019-09-09 | PXD013859 | Pride

Genetic dynamics in untreated chronic lymphocytic leukemia patients with either stable or progressive disease: a longitudinal study.

Project description:We investigated at two time points a longitudinal cohort of 27 untreated Chronic Lymphocytic Leukemia (CLL) patients with either stable or progressive disease. The sequenced genes included BCOR, EGR2, HIST1H1E, ITPKB, KRAS, MED12, NRAS, RIPK1, SAMHD1, ATM, BIRC3, BRAF, CHD2, DDX3X, DDX3Y, FBXW7, KIT, KLHL6, MAPK1, MYD88, NOTCH1, PIK3CA, POT1, SF3B1, TP53, XPO1 and ZMYM3, which were previously identified as mutated in CLL studies.

2019-11-05 | E-MTAB-8020 | biostudies-arrayexpress

Analysis of gene expression changes in KPT330-treated HMLE cells transduced to stably overexpress SNAI1

Project description:HMLE-SNAIL cell cultures were treated with KPT330 drug (KPT, 150 nanomolar) or vehicle (DMSO) for 24 hours, in parallel quadruplicates. KPT-330 is an Exportin 1 (XPO1) inhibitor with possible pluripotent or unexpected effects on cell signaling. Total RNA was isolated and analyzed in an Agilent two-color experiment, where four biological replicates of each condition were directly compared, expression ratios are KPT-treated condition relative to control (DMSO vehicle-treated) The experiment object was to identify genes that displayed significantly altered expression in response to KPT treatment inorder to confirm on-target drug impact and elucidate other potential effects in this cell line model.

2015-08-31 | E-GEOD-69326 | biostudies-arrayexpress

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