Science; doi:10.1126/science.1244851

Science; doi:10.1126/science.1244917

The use of thalidomide was discontinued as a sedative for pregnant women owing to its teratogenic properties. However, thalidomide and other derivatives such as lenalidomide have recently been shown to be highly effective for the treatment of multiple myeloma and other B-cell malignancies. Thalidomide has been shown to interact with cereblon (CBRN), a substrate recognition component of a Cul4 ubiquitin E3 ligase complex, but the basis for anti-myeloma activity downstream of CRBN remains unknown. Krönke et al. used a quantitative proteomic MS approach to perform ubiquitination profiling in lenalidomide-treated myeloma cells, and Lu et al. used a cell-based assay relying on an ORF library to detect proteins with lenalidomide-dependent changes in stability. Both studies found that lenalidomide promoted the binding of CBRN to two members of the Ikaros family of transcription factors, IKZF1 and IKZF3, which are required for B- and T-cell development. The CBRN-Ikaros interaction resulted in the ubiquitination and degradation of IKZF1 and IKZF3. Both groups identified unique residues on IKZF3 (Q147) and IKZF1 (Q146) that are necessary and sufficient for lenalidomide responsiveness. Knockdown of IKZF1 or IKZF3 reduced growth of lenalidomide-sensitive cell lines, whereas overexpression of a stabilized form of IKZF1 or IKZF3 conferred resistance to lenalidomide, suggesting that decreased IKZF1 and IKZF3 expression mediates the antimyeloma effects of lenalidomide.