Expression, mutation, and methylation of cereblon-pathway genes at pre- and post-lenalidomide treatment in multiple myeloma

Cancer Sci. 2020 Apr;111(4):1333-1343. doi: 10.1111/cas.14352. Epub 2020 Mar 12.


Cereblon (CRBN) is a target for immunomodulatory drugs. This study investigated the prognostic value of the expression of CRBN-pathway genes on the clinical relevance of lenalidomide (Len) treatment and evaluated the levels of CRBN-binding proteins and mutations in these genes after Len treatment. Forty-eight primary multiple myeloma cells were collected prior to treatment with Len and dexamethasone (Ld) and 25 paired samples were obtained post-Ld therapy. These tumor cells were used to determine the expression and mutated forms of the CRBN-pathway genes. Following normalization with CRBN levels, there was a significantly reduced IKZF1/CRBN ratio in samples that responded poorly to Ld therapy. Moreover, patients with low ratios of IKZF1/CRBN showed a significantly shorter progression-free survival (PFS) and overall survival (OS) than those with higher ratios. However, patients with high ratios of KPNA2/CRBN showed a significantly shorter PFS and OS than patients with lower ratios. Of the 25 paired samples analyzed, most samples showed a reduction in the expression of CRBN and an increase in IKZF1 gene expression. No mutations were observed in CRBN, IKZF1, or CUL4A genes in the post-Ld samples. In conclusion, a decreased expression of IKZF1 and increased expression of KPNA2 compared to that of CRBN mRNA predicts poor outcomes of Ld therapy.

Keywords: CRBN; IKZF1; KPNA2; lenalidomide; multiple myeloma.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics
  • Cullin Proteins / genetics
  • Dexamethasone / administration & dosage
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Ikaros Transcription Factor / genetics*
  • Immunomodulation
  • Lenalidomide / administration & dosage*
  • Lenalidomide / adverse effects
  • Male
  • Methylation
  • Middle Aged
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / genetics
  • Multiple Myeloma / pathology
  • Mutation
  • Prognosis
  • Progression-Free Survival
  • Ubiquitin-Protein Ligases
  • alpha Karyopherins / genetics*


  • Adaptor Proteins, Signal Transducing
  • Biomarkers, Tumor
  • CRBN protein, human
  • CUL4A protein, human
  • Cullin Proteins
  • IKZF1 protein, human
  • KPNA2 protein, human
  • alpha Karyopherins
  • Ikaros Transcription Factor
  • Dexamethasone
  • Ubiquitin-Protein Ligases
  • Lenalidomide