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

by McConkey, Marie , Krönke, Jan , Munshi, Nikhil , Heckl, Dirk , Hurst, Slater N. , Svinkina, Tanya , Udeshi, Namrata D. , Carr, Steven A. , Grauman, Peter , Comer, Eamon , Ciarlo, Christie , Ebert, Benjamin L , Li, Xiaoyu , Schenone, Monica , Schreiber, Stuart L. , Narla, Anupama , Hartman, Emily

in Amino acids / antineoplastic activity / Antineoplastic Agents - pharmacology / B lymphocytes / Cell Line, Tumor / Cell lines / drugs / fetal development / Gene expression / HEK293 Cells / Humans / Ikaros Transcription Factor - genetics / Ikaros Transcription Factor - metabolism / immunomodulation / Interleukin-2 - biosynthesis / Multiple myeloma / Multiple Myeloma - metabolism / myeloma / patients / Plasma cells / Proteins / Proteolysis / Proteomics / Quantitative genetics / Receptors / T lymphocytes / T-Lymphocytes - drug effects / T-Lymphocytes - metabolism / Thalidomide - analogs & derivatives / Thalidomide - pharmacology / Transcription factors / Tumors / ubiquitin-protein ligase / Ubiquitination / Ubiquitins

2014

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

2014

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

2014

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Journal Article

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

McConkey, Marie,

Krönke, Jan,

Munshi, Nikhil,

Heckl, Dirk,

Hurst, Slater N.,

Svinkina, Tanya,

Udeshi, Namrata D.,

Carr, Steven A.,

Grauman, Peter,

Comer, Eamon,

Ciarlo, Christie,

Ebert, Benjamin L,

Li, Xiaoyu,

Schenone, Monica,

Schreiber, Stuart L.,

Narla, Anupama,

Hartman, Emily

2014

Overview

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.

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Publisher

American Association for the Advancement of Science,The American Association for the Advancement of Science

Subject

Amino acids

/ antineoplastic activity

/ Antineoplastic Agents - pharmacology

/ B lymphocytes

/ Cell Line, Tumor

/ Cell lines

/ drugs