Science· 2013Q1
Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
- 1,851citations
- Q1SCImago
- 2013year
Short summary
Lenalidomide selectively targets and degrades lymphoid transcription factors IKZF1 and IKZF3 in multiple myeloma cells via the CRBN-CRL4 ubiquitin ligase.
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Key points
- Lenalidomide induces selective ubiquitination and degradation of IKZF1 and IKZF3 transcription factors.
- The CRBN-CRL4 ubiquitin ligase complex mediates lenalidomide's degradation of IKZF1 and IKZF3.
- IKZF1 and IKZF3 are essential transcription factors for multiple myeloma cell survival.
- A single amino acid substitution in IKZF3 confers resistance to lenalidomide-induced degradation and cell growth inhibition.
AI-generated from the title and abstract; the full text is not read.
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.
The authors' abstract, as published at the source. Science, 2013 · DOI ↗
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Field: Hematology
HematologyMedicine