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

Jan Krönke, Emma C. Fink, Paul W. Hollenbach, Kyle J. MacBeth, Slater N. Hurst, Namrata D. Udeshi, Philip P. Chamberlain, D. R. Mani, Hon Wah Man, Anita K. Gandhi, Tanya Svinkina, Rebekka K. Schneider, Marie McConkey, Marcus Järås, Elizabeth Griffiths, Meir Wetzler, Lars Bullinger, Brian E. Cathers, Steven A. Carr, Rajesh Chopra and Benjamin L. Ebert ()
Additional contact information
Jan Krönke: Brigham and Women’s Hospital
Emma C. Fink: Brigham and Women’s Hospital
Paul W. Hollenbach: Celgene Corporation
Kyle J. MacBeth: Celgene Corporation
Slater N. Hurst: Brigham and Women’s Hospital
Namrata D. Udeshi: Broad Institute of MIT and Harvard
Philip P. Chamberlain: Celgene Corporation
D. R. Mani: Broad Institute of MIT and Harvard
Hon Wah Man: Celgene Corporation
Anita K. Gandhi: Celgene Corporation
Tanya Svinkina: Broad Institute of MIT and Harvard
Rebekka K. Schneider: Brigham and Women’s Hospital
Marie McConkey: Brigham and Women’s Hospital
Marcus Järås: Brigham and Women’s Hospital
Elizabeth Griffiths: Roswell Park Cancer Institute
Meir Wetzler: Roswell Park Cancer Institute
Lars Bullinger: University Hospital of Ulm
Brian E. Cathers: Celgene Corporation
Steven A. Carr: Broad Institute of MIT and Harvard
Rajesh Chopra: Celgene Corporation
Benjamin L. Ebert: Brigham and Women’s Hospital

Nature, 2015, vol. 523, issue 7559, 183-188

Abstract: Abstract 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 CRL4CRBN), 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 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.

Date: 2015
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DOI: 10.1038/nature14610

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