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

Nature
Authors
Keywords
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.

Year of Publication
2015
Journal
Nature
Volume
523
Issue
7559
Pages
183-8
Date Published
2015 Jul 09
ISSN
1476-4687
URL
DOI
10.1038/nature14610
PubMed ID
26131937
PubMed Central ID
PMC4853910
Links
Grant list
P01CA108631 / CA / NCI NIH HHS / United States
R01 HL082945 / HL / NHLBI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
P01 CA066996 / CA / NCI NIH HHS / United States
P01 CA108631 / CA / NCI NIH HHS / United States
T32GM007753 / GM / NIGMS NIH HHS / United States
11566 / Cancer Research UK / United Kingdom
R01HL082945 / HL / NHLBI NIH HHS / United States