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

被引：495

作者：

Zhu, Yuan Xiao ^{[1
]}

Braggio, Esteban ^{[1
]}

Shi, Chang-Xin ^{[1
]}

Bruins, Laura A. ^{[1
]}

Schmidt, Jessica E. ^{[1
]}

Van Wier, Scott ^{[1
]}

Chang, Xiu-Bao ^{[2
]}

Bjorklund, Chad C. ^{[3
]}

Fonseca, Rafael ^{[1
]}

Bergsagel, P. Leif ^{[1
]}

Orlowski, Robert Z. ^{[3
]}

Stewart, A. Keith ^{[1
]}

机构：

[1] Mayo Clin, Div Hematol Oncol, Scottsdale, AZ 85259 USA

[2] Mayo Clin, Div Biochem, Scottsdale, AZ 85259 USA

[3] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Lymphoma Myeloma, Houston, TX 77030 USA

来源：

BLOOD | 2011年 / 118卷 / 18期

关键词：

IMPROVED SURVIVAL; MULTIPLE-MYELOMA; IDENTIFICATION; THALIDOMIDE; THERAPY; IMIDS;

D O I：

10.1182/blood-2011-05-356063

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 anti-myeloma 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. (Blood. 2011;118(18):4771-4779)

引用

页码：4771 / 4779

页数：9

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