Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS

Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4–RBX1–DDB1–CRBN (known as CRL4 CRBN ), resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4 CRBN . These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases. Lenalidomide, a derivative of thalidomide, is an effective drug for myelodysplastic syndrome; lenalidomide binds the CRL4 CRBN E3 ubiquitin ligase and promotes degradation of casein kinase 1a, on which the malignant cells rely for survival. Mechanism of action of lenalidomide Thalidomide was taken off the market when it was found to cause malformation in children whose mothers had taken it as a treatment for morning sickness in the late 1950s and early 1960s. Later it emerged that thalidomide and derivatives could be successfully used to treat certain haematopoietic disorders, and the thalidomide derivative lenalidomide has proved an effective therapy for myelodysplastic syndrome (MDS). Ben Ebert and colleagues now show why lenalidomide is particularly efficient in so-called del(5q) MDS — a frequent form of MDS carrying deletions in one copy of the chromosome 5q arm. They find that lenalidomide binds the CRL4 CRBN E3 ubiquitin ligase and promotes degradation of casein kinase 1α, which the malignant cells rely on for survival. In addition, a new analogue of thalidomide, CC-122, is shown to have greater potency than lenalidomide in inducing degradation of other CRBN substrates that are important in certain B cell malignancies.