Altered nuclear export signal recognition as a driver of oncogenesis Journal Article


Authors: Taylor, J.; Sendino, M.; Gorelick, A. N.; Pastore, A.; Chang, M. T.; Penson, A. V.; Gavrila, E. I.; Stewart, C.; Melnik, E. M.; Herrejon Chavez, F.; Bitner, L.; Yoshimi, A.; Lee, S. C. W.; Inoue, D.; Liu, B.; Zhang, X. J.; Mato, A. R.; Dogan, A.; Kharas, M. G.; Chen, Y.; Wang, D.; Soni, R. K.; Hendrickson, R. C.; Prieto, G.; Rodriguez, J. A.; Taylor, B. S.; Abdel-Wahab, O.
Article Title: Altered nuclear export signal recognition as a driver of oncogenesis
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.
Keywords: tumor; mutations; identification; localization; phase-i; nucleophosmin; crm1; selective inhibitor; selinexor; 1st-in-class
Journal Title: Cancer Discovery
Volume: 9
Issue: 10
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2019-10-01
Start Page: 1452
End Page: 1467
Language: English
ACCESSION: WOS:000489623800027
DOI: 10.1158/2159-8290.Cd-19-0298
PROVIDER: wos
PMCID: PMC6774834
PUBMED: 31285298
Notes: Article -- Source: Wos
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MSK Authors
  1. Rajesh Kumar Soni
    15 Soni
  2. Barry Stephen Taylor
    202 Taylor
  3. Michael Kharas
    59 Kharas
  4. Ahmet Dogan
    240 Dogan
  5. Matthew   Chang
    24 Chang
  6. Stanley Chun-Wei Lee
    41 Lee
  7. Alexander Vincent Penson
    35 Penson
  8. Alessandro   Pastore
    41 Pastore
  9. Daichi   Inoue
    21 Inoue
  10. Akihide   Yoshimi
    31 Yoshimi
  11. Justin   Taylor
    38 Taylor
  12. Bo Liu
    10 Liu
  13. Xiao Jing Zhang
    7 Zhang
  14. Anthony R Mato
    79 Mato
  15. Lillian Elizabeth Bitner
    10 Bitner
  16. Ella M. Melnik
    1 Melnik