Comment[ArrayExpressAccession] E-GEOD-31421 Public Release Date 2011-09-30 Investigation Title Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [expression profiling] Comment[Submitted Name] Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [expression profiling] Experiment Description The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the anti-myeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to and putatively resistant to lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity, and a possible biomarker for the clinical assessment of anti-myeloma efficacy. We included 15 samples from multiple myeloma cell lines. Date of Experiment Term Source Name EFO Term Source Version Term Source File http://www.ebi.ac.uk/efo/efo.owl Person Last Name Braggio Esteban Xiao Keith Person First Name Esteban Braggio Zhu Stewart Person Mid Initials Y A Person Email braggio.esteban@mayo.edu Person Affiliation Mayo Clinic Person Phone Person Fax Person Address Biochemistry, Mayo Clinic, 13208 East Shea Boulevard, MCRB 3-024, Scottsdale, AZ, USA Person Roles submitter Person Roles Term Source REF Person Roles Term Accession Number Normalization Type Normalization Term Accession Number Normalization Term Source REF Replicate Type Replicate Term Accession Number Replicate Term Source REF Experimental Design Experimental Design Term Accession Number Experimental Design Term Source REF Quality Control Type Quality Control Term Accession Number Quality Control Term Source REF Protocol Name P-GSE31421-1 P-GSE31421-5 P-GSE31421-4 P-GSE31421-2 P-GSE31421-3 P-GSE31421-6 Protocol Description ID_REF =
VALUE = MAS5.0 signal intensity GeneChips were scanned using the Affymetrix Genechip Scanner 3000. Following fragmentation, cRNA were hybridized for 16 hr at 45C on HG-U133A Plus2.0 GeneChip. Total RNA extraction was performed according to the manufacturer's instructions (Qiagen). Biotinylated cRNA were prepared according to the standard Affymetrix protocol from 0.5 ug total RNA. The data were analyzed with Microarray Suite version 5.0 (MAS 5.0) using Affymetrix default analysis settings as normalization method. Protocol Software Protocol Hardware Protocol Contact Protocol Type bioassay_data_transformation image_aquisition hybridization nucleic_acid_extraction labeling feature_extraction Protocol Term Source REF Protocol Term Accession Number Experimental Factor Name PROTOCOL CELL LINE Experimental Factor Type protocol cell line Experimental Factor Term Source REF Experimental Factor Term Accession Number Publication Title Publication Author List PubMed ID Publication DOI Publication Status Publication Status Term Source REF Publication Status Term Accession Number Comment[SecondaryAccession] GSE31421 Comment[GEOLastUpdateDate] 2011-10-06 Comment[AEExperimentType] transcription profiling by array Comment[GEOReleaseDate] 2011-09-29 Comment[ArrayExpressSubmissionDate] 2011-08-15 SDRF File E-GEOD-31421.sdrf.txt