Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Yuan Xiao Zhu1,
  2. Esteban Braggio1,
  3. Chang-Xin Shi1,
  4. Laura A. Bruins1,
  5. Jessica E. Schmidt1,
  6. Scott Van Wier1,
  7. Xiu-Bao Chang2,
  8. Chad C. Bjorklund3,
  9. Rafael Fonseca1,
  10. P. Leif Bergsagel1,
  11. Robert Z. Orlowski3, and
  12. A. Keith Stewart1
  1. Divisions of 1Hematology-Oncology and
  2. 2Biochemistry, Mayo Clinic, Scottsdale, AZ; and
  3. 3Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX

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.

  • Submitted May 20, 2011.
  • Accepted August 2, 2011.
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