Mechanism of lenalidomide in multiple myeloma and del(5q) MDS. Lenalidomide binds to CRBN, the substrate adaptor of the CRL4^CRBN E3 ubiquitin ligase. Lenalidomide induces the recruitment of specific substrates to CRL4^CRBN and their ubiquitination by this ligase. In multiple myeloma, the ubiquitination and subsequent proteasomal degradation of two B-cell transcription factors, IKZF1 and IKZF3, kills multiple myeloma cells. In del(5q) MDS, the ubiquitination and degradation of casein kinase 1A1 causes the death of del(5q) cells, because they express this protein at haploinsufficient levels. Yellow hexagons represent ubiquitin molecules.