The study investigates the biochemical mechanisms underlying the antitumor activity of lenalidomide, a drug used to treat multiple myeloma and other B cell malignancies. Lenalidomide is known to bind to and inhibit the cereblon ubiquitin ligase, which is associated with thalidomide's teratogenic effects. The researchers used a plasmid library to identify proteins that are destabilized by lenalidomide, focusing on the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). They found that lenalidomide-bound cereblon targets IKZF1 and IKZF3 for proteasomal degradation, which is both necessary and sufficient for lenalidomide's therapeutic effect. This suggests that the antitumor and teratogenic activities of thalidomide-like drugs may be dissociable. The study also highlights the role of IKZF1 and IKZF3 in B cell development and their importance in myeloma, providing insights into the mechanisms of lenalidomide's antimyeloma activity.The study investigates the biochemical mechanisms underlying the antitumor activity of lenalidomide, a drug used to treat multiple myeloma and other B cell malignancies. Lenalidomide is known to bind to and inhibit the cereblon ubiquitin ligase, which is associated with thalidomide's teratogenic effects. The researchers used a plasmid library to identify proteins that are destabilized by lenalidomide, focusing on the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). They found that lenalidomide-bound cereblon targets IKZF1 and IKZF3 for proteasomal degradation, which is both necessary and sufficient for lenalidomide's therapeutic effect. This suggests that the antitumor and teratogenic activities of thalidomide-like drugs may be dissociable. The study also highlights the role of IKZF1 and IKZF3 in B cell development and their importance in myeloma, providing insights into the mechanisms of lenalidomide's antimyeloma activity.