title: Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma.
abstract: Cereblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM). Using 2 different methodologies, we identified 244 CRBN binding proteins and established relevance to MM biology by changes in their abundance after exposure to lenalidomide. Proteins most reproducibly binding CRBN (>fourfold vs controls) included DDB1, CUL4A, IKZF1, KPNA2, LTF, PFKL, PRKAR2A, RANGAP1, and SHMT2. After lenalidomide treatment, the abundance of 46 CRBN binding proteins decreased. We focused attention on 2 of these-IKZF1 and IKZF3. IZKF expression is similar across all MM stages or subtypes; however, IKZF1 is substantially lower in 3 of 5 IMiD-resistant MM cell lines. The cell line (FR4) with the lowest IKZF1 levels also harbors a damaging mutation and a translocation that upregulates IRF4, an IKZF target. Clinical relevance of CRBN-binding proteins was demonstrated in 44 refractory MM patients treated with pomalidomide and dexamethasone therapy in whom low IKZF1 gene expression predicted lack of response (0/11 responses in the lowest expression quartile). CRBN, IKZF1, and KPNA2 levels also correlate with significant differences in overall survival. Our study identifies CRBN-binding proteins and demonstrates that in addition to CRBN, IKZF1, and KPNA2, expression can predict survival outcomes.
authors.affiliation: Division of Hematology-Oncology and.
authors.forename: Yuan Xiao
authors.initials: YX
authors.lastname: Zhu
authors.affiliation: Division of Hematology-Oncology and.
authors.forename: Esteban
authors.initials: E
authors.lastname: Braggio
authors.affiliation: Division of Hematology-Oncology and.
authors.forename: Chang-Xin
authors.initials: CX
authors.lastname: Shi
authors.affiliation: Division of Hematology-Oncology and.
authors.forename: K Martin
authors.initials: KM
authors.lastname: Kortuem
authors.affiliation: Division of Hematology-Oncology and.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Bruins
authors.affiliation: Division of Hematology-Oncology and.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Schmidt
authors.affiliation: Department of Biochemistry & Molecular Biology, College of Medicine, Mayo Clinic, Scottsdale, AZ;
authors.forename: Xiu-Bao
authors.initials: XB
authors.lastname: Chang
authors.affiliation: Department of Biochemistry & Molecular Biology, College of Medicine, Mayo Clinic, Scottsdale, AZ;
authors.forename: Paul
authors.initials: P
authors.lastname: Langlais
authors.affiliation: Center for Metabolic and Vascular Biology, Arizona State University, Tempe, AZ;
authors.forename: Moulun
authors.initials: M
authors.lastname: Luo
authors.affiliation: Division of Hematology-Oncology and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Jedlowski
authors.affiliation: Division of Biomedical Statistics and Informatics and.
authors.forename: Betsy
authors.initials: B
authors.lastname: LaPlant
authors.affiliation: Division of Biomedical Statistics and Informatics and.
authors.forename: Kristina
authors.initials: K
authors.lastname: Laumann
authors.affiliation: Division of Hematology-Oncology and.
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
authors.affiliation: Division of Hematology-Oncology and.
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.affiliation: Division of Hematology-Oncology and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Mikhael
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN; and.
authors.forename: Martha
authors.initials: M
authors.lastname: Lacy
authors.affiliation: Division of Hematology-Oncology and Division of Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, AZ.
authors.forename: Mia D
authors.initials: MD
authors.lastname: Champion
authors.affiliation: Division of Hematology-Oncology and.
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D017322:Clinical Trials, Phase II as Topic; D003907:Dexamethasone / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D051740:Ikaros Transcription Factor / Q000378:metabolism; D007155:Immunologic Factors / Q000494:pharmacology*; D047468:Immunoprecipitation; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D010447:Peptide Hydrolases / Q000378:metabolism*; D011379:Prognosis; D011446:Prospective Studies; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D015996:Survival Rate; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D028901:alpha Karyopherins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000893:Anti-Inflammatory Agents; D014408:Biomarkers, Tumor; C502543:CRBN protein, human; D002352:Carrier Proteins; C497239:IKZF1 protein, human; D007155:Immunologic Factors; C490630:KPNA2 protein, human; D028901:alpha Karyopherins; D051740:Ikaros Transcription Factor; D013792:Thalidomide; D003907:Dexamethasone; C467566:pomalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000077269:Lenalidomide