Back to Search
Start Over
Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma.
- Source :
-
Blood [Blood] 2014 Jul 24; Vol. 124 (4), pp. 536-45. Date of Electronic Publication: 2014 Jun 09. - Publication Year :
- 2014
-
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.<br /> (© 2014 by The American Society of Hematology.)
- Subjects :
- Adaptor Proteins, Signal Transducing
Anti-Inflammatory Agents pharmacology
Blotting, Western
Clinical Trials, Phase II as Topic
Dexamethasone pharmacology
Flow Cytometry
Follow-Up Studies
Humans
Ikaros Transcription Factor metabolism
Immunoprecipitation
Lenalidomide
Multiple Myeloma drug therapy
Multiple Myeloma mortality
Prognosis
Prospective Studies
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Survival Rate
Thalidomide analogs & derivatives
Thalidomide pharmacology
Tumor Cells, Cultured
Ubiquitin-Protein Ligases
alpha Karyopherins metabolism
Biomarkers, Tumor metabolism
Carrier Proteins metabolism
Drug Resistance, Neoplasm
Immunologic Factors pharmacology
Multiple Myeloma metabolism
Peptide Hydrolases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 124
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 24914135
- Full Text :
- https://doi.org/10.1182/blood-2014-02-557819