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

By J. Krönke, E. Fink, P. Hollenbach, K. Macbeth, Slater N. Hurst, N. Udeshi, P. Chamberlain, D. Mani, Man Hon Wah, A. Gandhi and 11 more. Nature, 2015

774 citations recorded by the source corpus.

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.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3585f16bf5fa7b10dd07f24f493a68eb52ceead9

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In Hematology

1. Benjamin L. Ebert
2. Nathanael S. Gray

In Molecular Biology

1. Yang Xie
2. Benjamin L. Ebert
3. Tarjei S. Mikkelsen
4. Nathanael S. Gray

Citations in the corpus

• Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN (2018, positive): “which the b-hairpin zinc-coordinating cysteines are separated by two, three, or four residues [C-x(2,4)-C], but only C-x(2)-C ZFs were found destabilized in the screen (Fig.”
• Acute pharmacological degradation of Helios destabilizes regulatory T cells (2021, positive): “Indeed, thalidomide analogs (also known as IMiDs, or immunomodulatory imide drugs) can induce the degradation of a variety of proteins, such as Ikaros (IKZF1) and Aiolos (IKZF3) 8,9 , casein kinase 1 α (CK1 α ) 10 , ZFP91 11 , SALL4 12,13 , and GSPT1 14 .”
• Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15 (2017, background): “In another example of how chemical structure can influence neosubstrate preference, CC-885 was identified in a screen of IMiD derivatives as catalyzing the recruitment of GSPT1, a translation termination factor essential for myeloid leukemia cell proliferation, to CUL4-CRBN (44).”