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Effects on gene expression of nuclear export inhibitor in control and TP53-knockdown cell line of mantle cell lymphoma

ABSTRACT: The TP53 wild-type cell line JVM2, representing mantle cell lymphoma (MCL), was transduced to create control or TP53 knockdown (KD) forms. These were then either left untreated or treated with KPT-185, a selective inhibitor of nuclear export (SINE) by XPO1, for gene expression profiling (GEP). Consistent with the observation that KPT-185 was equally toxic to both forms, the majority of gene expression changes resulting from KPT-185 treatment were similar for both forms, even though TP53 is known to be one of the cargo proteins of XPO1. GEP showed downregulation of genes involved in proliferation, consistent with findings of cell cycle analysis and supported by Western blot results. Quantitative proteomics revealed repression of ribosomal biogenesis to be a major TP53-independent effect of KPT-185.

ORGANISM(S): Homo sapiens

PROVIDER: GSE70479 | GEO | 2015/08/18

SECONDARY ACCESSION(S): PRJNA288798

REPOSITORIES: GEO

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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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Effects on gene expression of nuclear export inhibitor in control and TP53-knockdown cell line of mantle cell lymphoma

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