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

Krönke, Jan; Fink, Emma C.; Hollenbach, Paul W.; MacBeth, Kyle J.; Hurst, Slater N.; Udeshi, Namrata D.; Chamberlain, Philip P.; Mani, D. R.; Man, Hon Wah and Gandhi, Anita K., et al. (2015) In Nature 523(7559). p.183-188
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... (More)

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.

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Nature
volume
523
issue
7559
pages
183 - 188
publisher
Nature Publishing Group
external identifiers
  • scopus:84936930551
ISSN
0028-0836
DOI
10.1038/nature14610
language
English
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no
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deb43290-1961-4c5e-9ddd-7a2de65144c1
date added to LUP
2017-01-30 09:29:39
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2017-11-05 05:12:50
@article{deb43290-1961-4c5e-9ddd-7a2de65144c1,
  abstract     = {<p>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<sup>CRBN</sup>), 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<sup>CRBN</sup>. 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.</p>},
  author       = {Krönke, Jan and Fink, Emma C. and Hollenbach, Paul W. and MacBeth, Kyle J. and Hurst, Slater N. and Udeshi, Namrata D. and Chamberlain, Philip P. and Mani, D. R. and Man, Hon Wah and Gandhi, Anita K. and Svinkina, Tanya and Schneider, Rebekka K. and McConkey, Marie and Järås, Marcus and Griffiths, Elizabeth and Wetzler, Meir and Bullinger, Lars and Cathers, Brian E. and Carr, Steven A. and Chopra, Rajesh and Ebert, Benjamin L.},
  issn         = {0028-0836},
  language     = {eng},
  month        = {07},
  number       = {7559},
  pages        = {183--188},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS},
  url          = {http://dx.doi.org/10.1038/nature14610},
  volume       = {523},
  year         = {2015},
}