title: Rate of CRL4(CRBN) substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4.
abstract: Recent discoveries suggest that the critical events leading to the anti-proliferative activity of the IMiD immunomodulatory agents lenalidomide and pomalidomide in multiple myeloma (MM) cells are initiated by Cereblon-dependent ubiquitination and proteasomal degradation of substrate proteins Ikaros (IKZF1) and Aiolos (IKZF3). By performing kinetic analyses, we found that the downregulation or proteasomal degradation of Ikaros and Aiolos led to specific and sequential downregulation of c-Myc followed by IRF4 and subsequent growth inhibition and apoptosis. Notably, to ensure growth inhibition and cell death, sustained downregulation of Ikaros and Aiolos, c-Myc or IRF4 expression was required. In addition, we found that the half-maximal rate, rather than the final extent of Ikaros and Aiolos degradation, correlated to the relative efficacy of growth inhibition by lenalidomide or pomalidomide. Finally, we observed that all four transcription factors were elevated in primary MM samples compared with normal plasma cells. Taken together, our results suggest a functional link between Ikaros and Aiolos, and the pathological dysregulation of c-Myc and IRF4, and provide a new mechanistic understanding of the relative efficacy of lenalidomide and pomalidomide based on the kinetics of substrate degradation and downregulation of their downstream targets.
authors.affiliation: Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Bjorklund
authors.affiliation: Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: L
authors.initials: L
authors.lastname: Lu
authors.affiliation: Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kang
authors.affiliation: Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Hagner
authors.affiliation: Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Havens
authors.affiliation: Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: M
authors.initials: M
authors.lastname: Amatangelo
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Couto
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Breider
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ning
authors.affiliation: Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Gandhi
authors.affiliation: Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: T O
authors.initials: TO
authors.lastname: Daniel
authors.affiliation: Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: R
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: A
authors.initials: A
authors.lastname: Klippel
authors.affiliation: Translational Development, Celgene Corporation, Summit, NJ, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Thakurta
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D000099218:Interferon Regulatory Factor-4
chemical_list: D000970:Antineoplastic Agents; D051740:Ikaros Transcription Factor; D050835:Interferon Regulatory Factors; D000077269:Lenalidomide; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D013792:Thalidomide; D000099218:Interferon Regulatory Factor-4; C497239:IKZF1 protein, human; C106285:IKZF3 protein, human; C489427:MYC protein, human; C467566:pomalidomide