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

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 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.

• Authors: 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, Benjamin L Ebert
• Journal: Nature (Nature) Vol. 523 Issue 7559 Pg. 183-188 (Jul 09 2015) ISSN: 1476-4687 [Electronic] England
• PMID: 26131937 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Immunologic Factors
• Thalidomide
• Ubiquitin-Protein Ligases
• Casein Kinase I
• Peptide Hydrolases
• Lenalidomide

Topics

• Amino Acid Sequence
• Animals
• Casein Kinase I (genetics, metabolism)
• Cell Line
• Gene Expression Regulation (drug effects)
• HEK293 Cells
• Humans
• Immunologic Factors (pharmacology)
• Jurkat Cells
• K562 Cells
• Lenalidomide
• Mice
• Molecular Sequence Data
• Myelodysplastic Syndromes (genetics, physiopathology)
• Peptide Hydrolases (chemistry)
• Proteolysis (drug effects)
• Sequence Alignment
• Sequence Deletion
• Species Specificity
• Thalidomide (analogs & derivatives, pharmacology)
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination (drug effects)