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Cancer Discov. 2019 Jul 8. doi: 10.1158/2159-8290.CD-19-0298. [Epub ahead of print]

Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
3
Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Barrio Sarriena s/n, Leioa, Spain.
4
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin.
8
Microchemistry and Proteomics Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
9
Department of Communications Engineering, University of the Basque Country (UPV/EHU), Bilbao, Spain.
10
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
11
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. abdelwao@mskcc.org.

Abstract

Altered expression of XPO1, the main nuclear export receptor in eukaryotic cells, has been observed in cancer, and XPO1 has been a focus of anticancer drug development. However, mechanistic evidence for cancer-specific alterations in XPO1 function is lacking. Here, genomic analysis of 42,793 cancers identified recurrent and previously unrecognized mutational hotspots in XPO1. XPO1 mutations exhibited striking lineage specificity, with enrichment in a variety of B-cell malignancies, and introduction of single amino acid substitutions in XPO1 initiated clonal, B-cell malignancy in vivo Proteomic characterization identified that mutant XPO1 altered the nucleocytoplasmic distribution of hundreds of proteins in a sequence-specific manner that promoted oncogenesis. XPO1 mutations preferentially sensitized cells to inhibitors of nuclear export, providing a biomarker of response to this family of drugs. These data reveal a new class of oncogenic alteration based on change-of-function mutations in nuclear export signal recognition and identify therapeutic targets based on altered nucleocytoplasmic trafficking.SIGNIFICANCE: Here, we identify that heterozygous mutations in the main nuclear exporter in eukaryotic cells, XPO1, are positively selected in cancer and promote the initiation of clonal B-cell malignancies. XPO1 mutations alter nuclear export signal recognition in a sequence-specific manner and sensitize cells to compounds in clinical development inhibiting XPO1 function.

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