Journal
SCIENCE
Volume 343, Issue 6168, Pages 301-305Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1244851
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Funding
- NIH [R01HL082945, P01 CA108631]
- Leukemia and Lymphoma Society Scholar Award
- Evans Foundation grant
- Starr Cancer Consortium
- SPARC consortium
- National Human Genome Research Institute [RL1-HG004671]
- German Research Foundation (DFG) [Kr-3886/1-1]
- German Cancer Aid
- Celgene
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Lenalidomide 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.
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