Scientific Publications

Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells.

Publication TypeJournal Article
AuthorsKrönke, J., Udeshi ND, Narla A., Grauman P., Hurst SN, McConkey M., Svinkina T., Heckl D., Comer E., Li X., Ciarlo C., Hartman E., Munshi N., Schenone M., Schreiber SL, Carr SA, and Ebert BL
AbstractLenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, we found that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3. These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.
Year of Publication2014
JournalScience (New York, N.Y.)
Volume343
Issue6168
Pages301-5
Date Published (YYYY/MM/DD)2014/01/17
ISSN Number0036-8075
DOI10.1126/science.1244851
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/24292625?dopt=Abstract