Cereblon and Its Role in the Treatment of Multiple Myeloma by Lenalidomide or Pomalidomide

Abstract

Cereblon (CRBN) is part of the cullin 4-containing E3 ubiquitin ligase complex (CRL4CRBN) and functions as a target of thalidomide and its analogs (lenalidomide and pomalidomide) known as immunomodulatory drugs (IMiDs). The CRBN gene consists of 1329 base pairs, 11 exons, and encodes a protein of 443 amino acids. Exons 10-11 code for the binding site of IMiDs and exons 5-7 for the binding site of DNA damage binding protein 1 (DDB1). CRBN consists of three sub-domains, the amino-terminal domain, the helical bundle domain involved in DDB1 binding and the carboxy-terminal domain harbouring IMiD– binding hydrophobic pocket CRBN in the absence of IMiDs binds to its endogenous substrate proteinsand it leads to ubiquitination of these substrates by the CRL4CRBN and their degradation by proteasomes. However, in the presence of IMiDs, CRBN binds new substrate proteins, transcription factors IKZF1 (IKAROS) and IKZF3 (AILOS), for drug-induced ubiquitination by the CRL4CRBN and next degradation in proteasomes. The administration of IMiDs alters the specificity of the CRL4CRBN and affects simultaneously the levels of two groups of substrate proteins. IMiDs upregulate the levels of endogenous substrates (MEIS2 and CRBN) and decrease the amounts of new substrates (IKAROS family proteins). In the meantime we do not know all possible substrates of the CRL4CRBN because it depends on the cell type and proteins expressed. IMiDs have the anti-proliferative, anti-angiogenic and immunomodulatory activities and are efficient in several hematological malignancies as multiple myeloma, chronic lymphocytic leukemia, mantle lymphoma and isolated del (5q) myelodysplastic syndrome. Targeted knockdown of IKAROS and AILOS causes the decrease of myeloma survival factor IRF4 (interferon regulatory factor 4) and c-myc with the decrease in cell viability in multiple myeloma cells and the increase of interleukin-2 in T-cells and their co-stimulation, both similar to that after IMiDs treatment.