Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells

By J. Krönke, N. Udeshi, A. Narla, Peter V. Grauman, Slater N. Hurst, M. McConkey, Tanya Svinkina, D. Heckl, Eamon Comer, Xiaoyu Li and 7 more. Science, 2013

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Drug With a (Re)Purpose Thalidomide, once infamous for its deleterious effects on fetal development, has re-emerged as a drug of great interest because of its beneficial immunomodulatory effects. A derivative drug called lenalidomide significantly extends the survival of patients with multiple myeloma, but the molecular mechanisms underlying its efficacy remain unclear (see the Perspective by Stewart). Building on a previous observation that thalidomide binds to cereblon, a ubiquitin ligase, Lu et al. (p. 305, published online 28 November) and Krönke et al. (p. 301, published online 28 November) show that in the presence of lenalidomide, cereblon selectively targets two B cell transcription factors (Ikaros family members, IKZF1 and IKZF3) for degradation. In myeloma cell lines and patient cells, down-regulation of IKZF1 and IKZF3 was necessary and sufficient for the drug's anticancer activity. Thus, lenalidomide may act, at least in part, by “grepurposing” a ubiquitin ligase. A drug with potent activity in multiple myeloma patients acts by inducing degradation of two specific transcription factors. [Also see Perspective by Stewart] 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.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/bf4fc60d821257f664ef758f219b75586ad0adaa

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Citations in the corpus

Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS (2015, background): “b, Immunoblot of CK1α protein levels in the bone marrow (1,2) and peripheral blood (3,4) mononuclear cells of AML patients treated with lenalidomide as part of a clinical trial.”
Thalidomide‐induced teratogenesis: History and mechanisms (2015, background): “…with Cereblon and can selectively activate downstream targets Ikaros and Aiolos to be recruited for degradation and help mediate their action in multiple myeloma, further indicating that the anti-tumor and teratogenic actions of the drug can be dissociated (Kronke et al., 2014; Lu et al., 2014).”
Proteolysis Targeting Chimeras as Therapeutics and Tools for Biological Discovery (2020, positive): “The off-target effects of CRBN-recruiting PROTACs must be very carefully assessed, since the IMiD components, alone or incorporated into PROTACs, can induce the degradation of zinc finger CRBN neo-substrates (Fischer et al., 2014; Ishoey et al., 2018; Krönke et al., 2014; Matyskiela et al., 2016).”