XPO1(E571K) Mutation Modifies Exportin 1 Localisation and Interactome in B-Cell Lymphoma

SIMPLE SUMMARY: Almost 25% of patients with either primary mediastinal B-cell lymphoma (PMBL) or classical Hodgkin lymphoma (cHL) possess a recurrent mutation of the XPO1 gene encoding the major nuclear export protein. The aim of our study was to assess the molecular function of the mutant XPO1 protein. Using several cell models (including CRISPR–Cas9 edited cells) and high throughput techniques, we determined that the export capacity of the mutant XPO1 was not altered. However, mutant XPO1 accumulated in the cytoplasm due to its binding to importin β1 (or IPO1). The targeting of XPO1 is largely efficient for fighting haemopathies. The inhibition of IPO1 could open new therapeutic perspectives for B-cell lymphomas. ABSTRACT: The XPO1 gene encodes exportin 1 (XPO1) that controls the nuclear export of cargo proteins and RNAs. Almost 25% of primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) cases harboured a recurrent XPO1 point mutation (NM_003400, chr2:g61718472C>T) resulting in the E571K substitution within the hydrophobic groove of the protein, the site of cargo binding. We investigated the impact of the XPO1(E571K) mutation using PMBL/cHL cells having various XPO1 statuses and CRISPR–Cas9-edited cells in which the E571K mutation was either introduced or knocked-out. We first confirmed that the mutation was present in both XPO1 mRNA and protein. We observed that the mutation did not modify the export capacity but rather the subcellular localisation of XPO1 itself. In particular, mutant XPO1 bound to importin β1 modified the nuclear export/import dynamics of relevant cargoes.