You are here

Science DOI:10.1126/science.1244851

Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells.

Publication TypeJournal Article
Year of Publication2014
AuthorsKrönke, J, Udeshi, ND, Narla, A, Grauman, P, Hurst, SN, McConkey, M, Svinkina, T, Heckl, D, Comer, E, Li, X, Ciarlo, C, Hartman, E, Munshi, N, Schenone, M, Schreiber, SL, Carr, SA, Ebert, BL
JournalScience
Volume343
Issue6168
Pages301-5
Date Published2014 Jan 17
ISSN1095-9203
KeywordsAntineoplastic Agents, Cell Line, Tumor, HEK293 Cells, Humans, Ikaros Transcription Factor, Interleukin-2, Multiple Myeloma, Proteolysis, T-Lymphocytes, Thalidomide, Ubiquitination
Abstract

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.

URLhttp://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=24292625
DOI10.1126/science.1244851
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24292625?dopt=Abstract

Alternate JournalScience
PubMed ID24292625
PubMed Central IDPMC4077049
Grant ListR01 HL082945 / HL / NHLBI NIH HHS / United States
P01 CA078378 / CA / NCI NIH HHS / United States
P01 CA155258 / CA / NCI NIH HHS / United States
P01 CA108631 / CA / NCI NIH HHS / United States
P50 CA100707 / CA / NCI NIH HHS / United States
RL1- HG004671 / HG / NHGRI NIH HHS / United States
RL1 HG004671 / HG / NHGRI NIH HHS / United States
R01HL082945 / HL / NHLBI NIH HHS / United States