Lenalidomide acts by a novel drug mechanism-modulation of the substrate specificity of the CRL4(CRBN) E3 ubiquitin ligase. In multiple myeloma, lenalidomide induces the ubiquitination of IKZF1 and IKZF3 by CRL4(CRBN). Subsequent proteasomal degradation of these transcription factors kills multiple myeloma cells. In del(5q) myelodysplastic syndrome, lenalidomide induces the degradation of CK1α, which preferentially affects del(5q) cells because they express this gene at haploinsufficient levels. In the future, modulation of ubiquitin ligase function may enable us to target previously "undruggable" proteins.
Keyphrases
- multiple myeloma
- induced apoptosis
- cell cycle arrest
- acute lymphoblastic leukemia
- transcription factor
- newly diagnosed
- endoplasmic reticulum stress
- stem cell transplantation
- signaling pathway
- genome wide
- current status
- low dose
- genome wide identification
- dna methylation
- dna binding
- drug induced
- electronic health record