Lenalidomide promotes CRBN-mediated ubiquitination and degradation of IKZF1 and IKZF3

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Published: 8 Dec 2013
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Dr Jan Krönke - Brigham and Women's Hospital, Boston, USA

During a press conference at the 2013 ASH Annual Meeting, Dr Jan Krönke presents data from a recent study investigating lenalidomide.

While lenalidomide is an effective treatment commonly used for multiple myeloma and certain B-cell lymphomas, research has yet to fully explain how it works. Using a combination of experiments focused on cellular protein activity, investigators discovered that lenalidomide has a unique mechanism of action for a drug. Specifically, investigators concluded that the drug promotes binding of two lymphoid transcription factors, IKZF1 and IKZF3, to the CRBN-DDB1 ubiquitin ligase. This interaction leads to the selective degradation of these transcription factors, which are essential for multiple myeloma cells. Consistant with this mechanism, the researchers also observed that lenalidomide decreased IKZF1 and IKZF3 levels in human T cells, leading to activation of IL-2 expression, a known effect of the drug.