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Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells.
- Source :
-
Science (New York, N.Y.) [Science] 2014 Jan 17; Vol. 343 (6168), pp. 301-5. Date of Electronic Publication: 2013 Nov 29. - Publication Year :
- 2014
-
Abstract
- 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.
- Subjects :
- Cell Line, Tumor
HEK293 Cells
Humans
Ikaros Transcription Factor genetics
Interleukin-2 biosynthesis
Lenalidomide
Proteolysis
T-Lymphocytes drug effects
T-Lymphocytes metabolism
Thalidomide pharmacology
Ubiquitination
Antineoplastic Agents pharmacology
Ikaros Transcription Factor metabolism
Multiple Myeloma metabolism
Thalidomide analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1095-9203
- Volume :
- 343
- Issue :
- 6168
- Database :
- MEDLINE
- Journal :
- Science (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 24292625
- Full Text :
- https://doi.org/10.1126/science.1244851