Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide

Sci Rep. 2020 Mar 4;10(1):4012. doi: 10.1038/s41598-020-61027-w.


Pomalidomide, a derivative of thalidomide, is an effective treatment for multiple myeloma. The drug exerts its effects through CRBN, a component of the E3 ubiquitin ligase complex CRL4CRBN. To search for novel factors involved in the anti-cancer activity of pomalidomide, we performed a genome-wide shRNA library screen and identified 445 genes as those affecting pomalidomide sensitivity. Genes encoding components of the ubiquitin-proteasome pathway, such as subunits of the CRL4CRBN complex, the COP9 signalosome, and the 26S proteasome, were among the pomalidomide-affecting genes. Karyopherin beta 1 (KPNB1) was identified as a novel pomalidomide-affecting gene. KPNB1 was required for the nuclear import of CRBN and for the CRBN-directed, pomalidomide-dependent degradation of a clinically relevant substrate, the transcription factor Aiolos. By contrast, the cytoplasmic translation factor GSPT1 was degraded following treatment with the thalidomide derivative CC-885 only when CRBN was present in the cytoplasm, indicating that subcellular distribution of CRBN is critical for the efficacy of thalidomide-based medications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Cell Line, Tumor
  • Genome-Wide Association Study
  • Humans
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism*
  • Multiple Myeloma / pathology
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Phenylurea Compounds / pharmacology
  • Thalidomide / analogs & derivatives*
  • Thalidomide / pharmacology
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*


  • Adaptor Proteins, Signal Transducing
  • CC-885
  • CRBN protein, human
  • Neoplasm Proteins
  • Phenylurea Compounds
  • Thalidomide
  • pomalidomide
  • Ubiquitin-Protein Ligases