Abstract
8540 Background: Cereblon (CRBN) binding mediates immunomodulatory drug (IMiD) action in MM. Methods: We identified CRBN binding proteins in the presence or absence of IMiD and examined the clinical significance of binding proteins. Results: The abundance of 46 CRBN binding proteins deceased after IMiDs and the most downregulated proteins include Ikaros transcription factors IKZF1 and IZKF3 (recently identified as rapidly downregulated subsequent to cereblon-IMiD interaction). We then explored the clinical significance of IKZF1/IKZF3 in MM. IZKF gene expression was similar across all MM stages or subtypes however on western blot in a subset of IMiD resistant cell lines IKZF1 is substantially lower. Genetic mutation in IZKF1/3 is observed in < 1% of MM patients however 6/69 MM cell lines (8.7%) have nonsynonymous SNVs including a L208R substitution and codon deletion in the FR4 cell line which has very low levels of IZKF1 and is highly IMiD resistant. Recurrent SNV at Q156K (XG1 and H1112) and at G158R in ...
Published Version
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