Cereblon (CRBN) is the target protein receptor on the CRL4CRBN E3 ligase complex in the ubiquitin-proteasome system that includes Cul4, DDB1, and Roc1.1-3 CRBN is expressed in a variety of tissues, with the highest levels detected in T and B cells among other immune cells.4,5 Preclinical studies suggest that immunomodulatory agents co-opt CRBN to mediate the ubiquitination and proteasomal degradation of substrate proteins.2,3,6-11 In preclinical studies, this mechanism has been shown to underlie the anti-proliferative and immunomodulatory activities of these agents in malignancies, including multiple myeloma, lymphoma, and del(5q) myelodysplastic syndromes.2,3,6-10 The redirection of CRBN by immunomodulatory agents has been shown to have tumoricidal effects in non-Hodgkin lymphoma and multiple myeloma through inhibition of expression of oncogenes, such as IRF4.9,12,13 In del(5q) myelodysplastic syndromes, immunomodulatory agent regulation of the CRL4CRBN complex has been shown to induce ubiquitination of casein kinase 1A1 (CK1α), resulting in its degradation.10 In multiple myeloma, there are tumorcidal, immunomodulatory, and anti-stromal support activities exhibited through modulation of the CRL4CRBN complex.14 Redirection of CRBN and the associated modulation of ubiquitination of proteins, as demonstrated in vitro, provide a molecular basis for the pharmacological activity of these immunomodulatory agents.

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