Lenalidomide Acts in Myeloma by Degrading Lymphoid Transcription Factors IKZF1 and IKZF3

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The mechanism of action of lenalidomide (Revlimid) in multiple myeloma and other B-cell neoplasms remains largely uncharacterized. In a study reported in Science, Krönke and colleagues identified one of the effects of lenalidomide in this setting.

Use of quantitative proteomics showed that lenalidomide caused selective ubiquitination and degradation of the lymphoid transcription factors IKZF1 and IKZF3—critical transcription factors in multiple myeloma—via the CRBN-CRL4 ubiquitin ligase. A single amino acid substitution in IKZF3 was shown to result in resistance to lenalidomide-induced degradation and to prevent lenalidomide-induced inhibition of cell growth. Further, it was shown that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3.

The investigators concluded, “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.” ■

Krönke J, et al: Science 343:301-305, 2014.




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