Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide

Yuan Xiao Zhu, Esteban D Braggio, Chang Xin Shi, Laura A. Bruins, Jessica E. Schmidt, Scott Van Wier, Xiu-Bao D Chang, Chad C. Bjorklund, Rafael Fonseca, Peter Leif Bergsagel, Robert Z. Orlowski, Alexander Keith Stewart

Research output: Contribution to journalArticle

349 Citations (Scopus)

Abstract

The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their antitumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the antimyeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells, but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone, and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion, further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to, and putatively resistant to, lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity and a possible biomarker for the clinical assessment of antimyeloma efficacy.

Original languageEnglish (US)
Pages (from-to)4771-4779
Number of pages9
JournalBlood
Volume118
Issue number18
DOIs
StatePublished - Nov 3 2011

Fingerprint

Thalidomide
Melphalan
Biomarkers
Gene expression
Pharmaceutical Preparations
Dexamethasone
lenalidomide
pomalidomide
Cells
Gene Expression
Cell Line
Therapeutics
Bortezomib
interferon regulatory factor-4

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. / Zhu, Yuan Xiao; Braggio, Esteban D; Shi, Chang Xin; Bruins, Laura A.; Schmidt, Jessica E.; Van Wier, Scott; Chang, Xiu-Bao D; Bjorklund, Chad C.; Fonseca, Rafael; Bergsagel, Peter Leif; Orlowski, Robert Z.; Stewart, Alexander Keith.

In: Blood, Vol. 118, No. 18, 03.11.2011, p. 4771-4779.

Research output: Contribution to journalArticle

Zhu, YX, Braggio, ED, Shi, CX, Bruins, LA, Schmidt, JE, Van Wier, S, Chang, X-BD, Bjorklund, CC, Fonseca, R, Bergsagel, PL, Orlowski, RZ & Stewart, AK 2011, 'Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide', Blood, vol. 118, no. 18, pp. 4771-4779. https://doi.org/10.1182/blood-2011-05-356063
Zhu, Yuan Xiao ; Braggio, Esteban D ; Shi, Chang Xin ; Bruins, Laura A. ; Schmidt, Jessica E. ; Van Wier, Scott ; Chang, Xiu-Bao D ; Bjorklund, Chad C. ; Fonseca, Rafael ; Bergsagel, Peter Leif ; Orlowski, Robert Z. ; Stewart, Alexander Keith. / Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. In: Blood. 2011 ; Vol. 118, No. 18. pp. 4771-4779.
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