Lenalidomide induces ubiquitination and degradation of ck1[alpha] in del(5q) mds

• Autores: Jan Krönke, Emma C. Fink, P. W. Hollenbach, Kyle J. MacBeth, Slater N. Hurst, Namrata D. Udeshi
• Localización: Nature: International weekly journal of science, ISSN 0028-0836, Vol. 523, Nº 7559, 2015, págs. 183-188
• Idioma: inglés
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• Resumen

  • 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 (CK1[alpha]) by the E3 ubiquitin ligase CUL4–RBX1–DDB1–CRBN (known as CRL4CRBN), resulting in CK1[alpha] degradation. CK1[alpha] 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 CK1[alpha]. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4CRBN. 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.