Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma

Yuan Xiao Zhu, Esteban Braggio, Chang Xin Shi, K. Martin Kortuem, Laura A. Bruins, Jessica E. Schmidt, Xiu Bao Chang, Paul Langlais, Moulun Luo, Patrick Jedlowski, Betsy LaPlant, Kristina Laumann, Rafael Fonseca, P. Leif Bergsagel, Joseph Mikhael, Martha Lacy, Mia D. Champion, A. Keith Stewart

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

Cereblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM). Using 2 different methodologies, we identified 244 CRBN binding proteins and established relevance to MM biology by changes in their abundance after exposure to lenalidomide. Proteins most reproducibly binding CRBN (>fourfold vs controls) included DDB1, CUL4A, IKZF1, KPNA2, LTF, PFKL, PRKAR2A, RANGAP1, and SHMT2. After lenalidomide treatment, the abundance of 46 CRBN binding proteins decreased. We focused attention on 2 of these-IKZF1 and IKZF3. IZKF expression is similar across all MM stages or subtypes; however, IKZF1 is substantially lower in 3 of 5 IMiD-resistant MM cell lines. The cell line (FR4) with the lowest IKZF1 levels also harbors a damaging mutation and a translocation that upregulates IRF4, an IKZF target. Clinical relevance of CRBN-binding proteins was demonstrated in 44 refractory MM patients treated with pomalidomide and dexamethasone therapy in whom low IKZF1 gene expression predicted lack of response (0/11 responses in the lowest expression quartile). CRBN, IKZF1, and KPNA2 levels also correlate with significant differences in overall survival. Our study identifies CRBN-binding proteins and demonstrates that in addition to CRBN, IKZF1, and KPNA2, expression can predict survival outcomes.

Original languageEnglish (US)
Pages (from-to)536-545
Number of pages10
JournalBlood
Volume124
Issue number4
DOIs
StatePublished - Jul 24 2014

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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