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Cancer -associated mutations in XPO1 transform cells through altered nuclear export signal recognition

ABSTRACT: 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 IB 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE120231 | GEO | 2021/09/01

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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Cancer -associated mutations in XPO1 transform cells through altered nuclear export signal recognition

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