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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • 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
  • Elizabeth Griffiths
  • Meir Wetzler
  • Lars Bullinger
  • Brian E. Cathers
  • Steven A. Carr
  • Rajesh Chopra
  • Benjamin L. Ebert
Enheter & grupper
Externa organisationer
  • Celgene Corporation
  • Brigham and Women's Hospital / Harvard Medical School
  • Roswell Park Cancer Institute
  • University Hospital of Ulm
  • Helsinki University Central Hospital
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik
  • Hematologi
Originalspråkengelska
Sidor (från-till)183-188
TidskriftNature
Volym523
Utgivningsnummer7559
StatusPublished - 2015 jul 9
PublikationskategoriForskning
Peer review utfördJa