Altered nuclear export signal recognition as a driver of oncogenesis

Justin Taylor, Maria Sendino, Alexander N. Gorelick, Alessandro Pastore, Matthew T. Chang, Alexander V. Penson, Elena I. Gavrila, Connor Stewart, Ella M. Melnik, Florisela Herrejon Chavez, Lillian Bitner, Akihide Yoshimi, Stanley Chun Wei Lee, Daichi Inoue, Bo Liu, Xiao J. Zhang, Anthony R. Mato, Ahmet Dogan, Michael G. Kharas, Yuhong ChenDemin Wang, Rajesh K. Soni, Ronald C. Hendrickson, Gorka Prieto, Jose A. Rodriguez, Barry S. Taylor, Omar Abdel-Wahab

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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 devel-opment. 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.

Original languageEnglish (US)
Pages (from-to)1452-1467
Number of pages16
JournalCancer discovery
Volume9
Issue number10
DOIs
StatePublished - Oct 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

Fingerprint

Dive into the research topics of 'Altered nuclear export signal recognition as a driver of oncogenesis'. Together they form a unique fingerprint.

Cite this