title: 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.affiliation: Brigham and Women's Hospital, Division of Hematology, Boston, Massachusetts, USA.|University Hospital of Ulm, Department of Internal Medicine III, Ulm, Germany.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Krönke
authors.affiliation: Brigham and Women's Hospital, Division of Hematology, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Fink
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hollenbach
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: MacBeth
authors.affiliation: Brigham and Women's Hospital, Division of Hematology, Boston, Massachusetts, USA.
authors.forename: Slater N
authors.initials: SN
authors.lastname: Hurst
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Namrata D
authors.initials: ND
authors.lastname: Udeshi
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Philip P
authors.initials: PP
authors.lastname: Chamberlain
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Mani
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Hon Wah
authors.initials: HW
authors.lastname: Man
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Anita K
authors.initials: AK
authors.lastname: Gandhi
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Svinkina
authors.affiliation: Brigham and Women's Hospital, Division of Hematology, Boston, Massachusetts, USA.
authors.forename: Rebekka K
authors.initials: RK
authors.lastname: Schneider
authors.affiliation: Brigham and Women's Hospital, Division of Hematology, Boston, Massachusetts, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: McConkey
authors.affiliation: Brigham and Women's Hospital, Division of Hematology, Boston, Massachusetts, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Järås
authors.affiliation: Roswell Park Cancer Center, Buffalo, New York, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Griffiths
authors.affiliation: Roswell Park Cancer Center, Buffalo, New York, USA.
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
authors.affiliation: University Hospital of Ulm, Department of Internal Medicine III, Ulm, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Cathers
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Brigham and Women's Hospital, Division of Hematology, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D019169:Jurkat Cells; D020014:K562 Cells; D000077269:Lenalidomide; D051379:Mice; D008969:Molecular Sequence Data; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000503:physiopathology*; D010447:Peptide Hydrolases / Q000737:chemistry; D059748:Proteolysis / Q000187:drug effects; D016415:Sequence Alignment; D017384:Sequence Deletion; D013045:Species Specificity; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects*
chemical_list: D007155:Immunologic Factors; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D047389:Casein Kinase I; D010447:Peptide Hydrolases; D000077269:Lenalidomide