title: Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells.
abstract: Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, we found that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3. These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.
authors.affiliation: Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Krönke
authors.forename: Namrata D
authors.initials: ND
authors.lastname: Udeshi
authors.forename: Anupama
authors.initials: A
authors.lastname: Narla
authors.forename: Peter
authors.initials: P
authors.lastname: Grauman
authors.forename: Slater N
authors.initials: SN
authors.lastname: Hurst
authors.forename: Marie
authors.initials: M
authors.lastname: McConkey
authors.forename: Tanya
authors.initials: T
authors.lastname: Svinkina
authors.forename: Dirk
authors.initials: D
authors.lastname: Heckl
authors.forename: Eamon
authors.initials: E
authors.lastname: Comer
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.forename: Christie
authors.initials: C
authors.lastname: Ciarlo
authors.forename: Emily
authors.initials: E
authors.lastname: Hartman
authors.forename: Nikhil
authors.initials: N
authors.lastname: Munshi
authors.forename: Monica
authors.initials: M
authors.lastname: Schenone
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D007376:Interleukin-2 / Q000096:biosynthesis; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000378:metabolism*; D059748:Proteolysis; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; C497239:IKZF1 protein, human; C106285:IKZF3 protein, human; D007376:Interleukin-2; D051740:Ikaros Transcription Factor; D013792:Thalidomide; D000077269:Lenalidomide