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

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. Overall design: Changes in amino acid charges created by mutations in XPO1 lead to sequence-specific effects on nuclear export signal recognition and promote malignant transformation.