title: The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins.
abstract: Thalidomide-like drugs such as lenalidomide are clinically important treatments for multiple myeloma and show promise for other B cell malignancies. The biochemical mechanisms underlying their antitumor activity are unknown. Thalidomide was recently shown to bind to, and inhibit, the cereblon ubiquitin ligase. Cereblon loss in zebrafish causes fin defects reminiscent of the limb defects seen in children exposed to thalidomide in utero. Here we show that lenalidomide-bound cereblon acquires the ability to target for proteasomal degradation two specific B cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). Analysis of myeloma cell lines revealed that loss of IKZF1 and IKZF3 is both necessary and sufficient for lenalidomide's therapeutic effect, suggesting that the antitumor and teratogenic activities of thalidomide-like drugs are dissociable.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.forename: Richard E
authors.initials: RE
authors.lastname: Middleton
authors.forename: Huahang
authors.initials: H
authors.lastname: Sun
authors.forename: MarkVic
authors.initials: M
authors.lastname: Naniong
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ott
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D013723:Teratogens / Q000494:pharmacology*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C502543:CRBN protein, human; C497239:IKZF1 protein, human; C106285:IKZF3 protein, human; D013723:Teratogens; D051740:Ikaros Transcription Factor; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000077269:Lenalidomide